FR2493320A1 - NOVEL CARBOSTYRILE DERIVATIVES USEFUL AS CARDIOTONIC, PROCESSES FOR PREPARING THEM AND MEDICAMENTS CONTAINING SAME - Google Patents

Abstract

THE INVENTION CONCERNS NEW PIPERAZINYLCARBOSTYRILES OF GENERAL FORMULA: (CF DRAWING IN BOPI) AND THEIR PREPARATION PROCESS. APPLICATIONS: TONICARDIAC MEDICINAL PRODUCTS, ESPECIALLY IN UNIT DOSAGE FORMS CONTAINING FROM 2 TO 200MG OF ACTIVE PRODUCT.

Description

The present invention relates to certain carbostyril derivatives and

  pharmaceutically acceptable salts thereof, which are useful as cardiotonic agents, processes for their preparation and

drugs containing them.

  Various carbostyril derivatives having hypotensive, blood platelet coagulation inhibitory or antiallergic activity are known, as described in Japanese Patent Applications (OPI) Nos. 130589/79, 135785/79, 138585/79, 141785 / 79

  76872/80, 49319/80, 53283/80, 53284 / and 83781/80.

  In addition, documents EP-AI-7525 and EP-AI-8014 disclose isoquinoline derivatives which possess

cardiac and circulatory.

  However, the carbostyril derivatives of the invention have a different structure from that of the carbostyril derivatives.

and conventional isoquinoline.

  The subject of the invention is novel carbohydrate derivatives

  styrile endowed with cardiotonic activity.

  The subject of the invention is also medicaments containing the carbostyril derivative in an effective amount such as

cardiotonic.

  The invention also relates to a process for preparing a carbostyril derivative and its pharmaceutically acceptable salts. The present invention which results from research

  in one of its aspects, a carbon derivative

styril of formula

N R3

(T) N OR

R R

  in which R 1 represents a hydrogen atom, an alkyl group

  lower alkenyl, lower alkynyl, or phenyl-

  lower alkyl; R2 represents a hydrogen atom at a lower alkoxy group, R represents a hydrogen atom or a lower alkanoyl group,

  a furoyl group, a pyridylcarbonyl group, an alkane-

  lower sulfonyl group, a lower alkoxycarbonyl group, a lower alkoxycarboxyalkyl group, a phenylsulfonyl group which may be substituted by a lower alkyl group on the benzene ring, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower phenylcarbonyla group,

  a lower phenylalkyl group, or a lower phenylalkanoyl group

  each of said phenylcarbonyl, lower phenylalkyl,

  and lower phenylalkanoyl which may be substituted on its benign ring.

  with 1 to 3 substituents selected from halogen atoms

  gene, lower alkoxy, lower alkyl, cyano, nitro, amino, hydroxy, lower alkanoylamino, lower alkylthio and lower alkanoyloxy or lower alkylenedioxy; and the 3-4 bond of the carbostyril ring being a single bond or

  double, and their pharmaceutically acceptable salts.

  According to another of its aspects, the invention relates to a cardiotonic drug containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount effective as a cardiotonic. According to another of its aspects, the invention relates to processes for the preparation of the compounds of formula (I) and

  their pharmaceutically acceptable salts.

  The compounds of formula (I) above and their pharmaceutically acceptable salts have a cardiac muscle stimulating effect or a positive inotropic effect and a coronary blood flow enhancing activity, and are useful as cardiotonic agents for treating heart disease, such as heart failure, etc. They have the advantage that they do not increase

  not, or only slightly, the heart rate.

  The term "lower alkyl" as used herein means

  description for a straight or branched chain alkyl group

  C1-C6, such as methyl, ethyl, propyl, isopropyl,

  butyl, tert-butyl, pentyl, hexyl, etc.

  The term "lower alkenyl" is understood to mean

  describes a straight chain alkenyl group

  or branched C2-C6, such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl, etc.

  The term "lower alkynyl" is understood to mean

  describes a straight chain alkynyl group

  or branched C2-C such as ethylyl, 2-propynyl, 2-buty-n-butyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl, etc. The term "lower phenylalkyl" refers to the

  present description to denote a phenyl-lower alkyl group.

  with a C1-C6 straight or branched chain alkyl group

  such as benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenyl-

  propyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenyl-

  pentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, etc.

  The term "lower alkoxy" is understood to mean

  describes a straight chain alkoxy group

  or branched C1-C6, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc. The term "lower alkanoyl" means in the

  present description to denote a chain alkanoyl group

  straight or branched C1-C6, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, etc. The term "halogen" is used in this

  description for fluorine, chlorine, bromine and iodine.

  The term "lower alkylenedioxy" means in

  the present description to designate an alkylenedioxy group

  C1-C4 straight or branched chain, such as methylene

  dioxy, ethylenedioxy, trimethylenedioxy, etc. The term "lower alkanesulfonyl" means in

  the present description to designate an alkanesulfonyl group

  straight or branched C1-C6 chain, such as a methane group,

  sulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl,

  butanesulfonyl, tert-butanesulfonyl, pentanesulfonyl, hexane

  sulfonyl, etc. The term "lower alkoxycarbonyl" means in

  the present description to designate an alkoxycarbonyl group

  C1-C6 straight or branched chain, such as a group

  methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy

  carbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.

  The term "lower alkoxycarbonyl-lower alkyl"

  "in this description means to designate a group

  (C1-C6 alkoxy) -carbonyl (C1-C6) alkyl, such as a group

  methoxycarbonylmethyl, 3-methoxycarbonylpropyl, 4-thoxycarbonyl-

  butyl, 6-propoxycarbonylhexyl, 5-isopropoxycarbonylpentyl, 1,1-

  dimethyl-2-butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonyl

  propyl, 2-pentyloxycarbonylethyl, hexyloxycarbonylmethyl.

  The term "phenylsulfonyl group which may be

  substituted with the benzene ring by a lower alkyl group

  in the present description to denote a phenyl group.

  sulfonyl, which may be substituted for the benzene ring by a C1-C6 straight or branched alkyl group, such as a group

  phenylsulfonyl, p-toluenesulfonyl, 2-methylphenylsulfonyl, 3-ethyl-

  phenylsulfonyl, 4-propylphenylsulfonyl, 2-butylphenylsulfonyl,

  3-tert-butylphenylsulfonyl, 4-pentylphenylsulfonyl, 2-hexylphenyl-

  sulfonyl, etc. The term "phenylcarbonyl group substituted with 1 to 3 substituents selected from halogen atoms, lower alkoxy, lower alkyl, cyano, nitro, amino, hydroxy,

  lower alkanoylamino, lower alkylthio, and lower alkanoyloxy

  or a lower alkylenedioxy group "means in the

  present description to denote a phenylcarbonyl group

  substituted with 1 to 3 substituents selected from halo

  C1-C6 straight or branched chain alkoxy, C1-C6 straight chain or branched chain alkyl, cyanon, nitro, amino,

  hydroxy, straight-chain or branched C1-C6 alkanoylamino, alkyl-

  C1-C6 straight or branched chain thio and C1-C6 straight or branched chain alkanoyloxy, or alkylenedioxy group

  C1-C4, such as 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl,

  benzoyl, 2-fluorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2bromobenzoyl, 3-bromobenzoyl, 4-bromobenzoyl, 2-iodobenzoyl,

  4-iodobenzoyl, 3,5-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,4-di-

  chlorobenzoyl, 3,4-difluorobenzoyl, 3,5-dibromobenzoyl, 3,4,5-

  trichlorobenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methyl-

  benzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 3-iso-

  propylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzyl, 2,5-dimethyl-

  benzoyl, 3,4,5-trimethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl

  zoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl,

  4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-hexyloxybenzoyl, 3,4-

  dimethoxybenzoyl, 3,4-diethoxybenzoyl, 3,4,5-trimethoxybenzoyl,

  2,5-dimethoxybenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitro-

  benzoyl, 2,4-dinitrobenzoyl, 2-aminobenzoyl, 3-aminobenzoyl,

  4-aminobenzoyl, 2,4-diaminobenzoyl, 2-cyanobenzoyl, 3-cyano-

  benzoyl, 4-cyanobenzoyl, 2,4-dicyanobenzoyl, 3,4-methylenedioxy-

  benzoyl, 3,4-ethylenedioxybenzoyl, 2,3-methylenedioxybenzoyl,

  3-methyl-4-chlorobenzoyl, 2-chloro-6-methylbenzoyl, 2-methoxy-3-

  chlorobenzoyl, 2-hydroxybenzoyl, 3-hydroxybenzoyl, 4-hydroxy-

  benzoyl, 3,4-dihydroxybenzoyl, 3,4,5-trihydroxybenzoyl, 2-formyl-

  aminobenzoyl, 3-acetylaminobenzoyl, 4-acetylaminobenzoyl,

  2-acetylaminobenzoyl, 3-propionylaminobenzoyl, 4-butyrylamino

  benzoyl, 2-isoburyrylaminobenzoyl, 3-pentanoylaminobenzyl,

  3-tert-butylcarbonylaminobenzoyl, 4-hexanoylaminobenzoyl, 2-methyl-

  thiobenzoyl, 3-methylthiobenzoyl, 2,6-dicetylmilnobezoyl, 4-methylthiobenzoyl

  zoyl, 2-amylthbenyl, 3-ethylthidezoyl, 3-propylthiobenzayl, 4-hexylthio-

  benzoyl, 3,4-dimethylthiobenzoyl, 2,5-dimethylthiobenzoyl, 3,4,5-

  trimethylthiobenzoyl, 2-formyloxybenzoyl, 3-acetyloxybenzoyl, 4acetyloxybenzoyl, 2-acetyloxybenzoyl, 3-propionyloxybenzoyl,

  4-butyryloxybenzoyl, 2-isobutyryloxybenzoyl, 3-pentanoyloxy

  benzoyl, 3-tert-butyryloxybenzoyl, 4-hexanoyloxybenzoyl, 3,4-

  diacetyloxybenzoyl, 3,4,5-triacetyloxybenzoyl, etc. The term "lower phenylalkyl group substituted with 1 to 3 substituents selected from halogen atoms and lower alkoxy, lower alkyl, cyano; nitro, amino,

  hydroxy, lower alkanoylamino, lower alkylthio and alkanoyl-

  lower oxy or lower alkylenedioxy group "refers to

  in the present disclosure, a lower phenylalkyl group

  having 1 to 3 substituents selected from halogen atoms, straight-chained or branched C1-C6 alkoxy, straight-chain or branched C1-C6 alkyl, cyano, nitro, amino hydroxy, straight-chain or branched alkanoylamino C1-C6 alkylthio a

249332O

  straight or branched chain C1-C6 or alkanoyloxy A straight or branched chain. C1-C6, or a C1-C6 alkylenedioxy group,

  such as 2-chlorobenzoyl, 2- (3-chlorophenyl) ethyl, 1- (4-

  chlorophenyl) ethyl, 3- (2-fluorophenyl) propyl, 4- (3-fluorophenyl) -

  butyl, 1,1-dimethyl-2- (4-fluorophenyl) ethyl, 5- (2-bromophenyl) -

  pentyl, 5r (2-bromopheryl) pentyl, 6C3-bromopheryl) hexyl, 2-methyl-

  3- (4-bromophenyl) propyl, 3-iodobanzoyl, 2- (4-iodophenyl) ethyl, 1- (3,5-dichlorophenyl) ethyl, 2- (3,4-dichlorophenyl) ethyl, 3- (2,6

  dichiorophenyl) propyl, 4- (3,4-dichlorophenyl) butyl, 1,1-dimethyl-

  2- (3,4-difluorophenyl) ethyl, 5- (3,5-dibromophenyl) phenyl, 6 <3,4,5-

  trichlorophenyl) hexyl, 4-methylbenzoyl, 2- (2-methylphenyl) -

  ethyl, 1- (3-methylphenyl) ethyl, 3- (3-ethylphenyl) propyl, 4- (2-

  ethylphenyl) butyl, 5- (4-ethylphenyl) pentyl, 6 (3-isopropylphenyl) -

  hexyl, 2-methyl-3- (4-hexylphenyl) propyl, 2- (3,4-dimethylphenyl) -

  ethyl, 2- (2,5-dimethylphenyl) ethyl, 2- (3,4,5-trimethylphenyl) -

  ethyl, 4-methoxybenzoyl, 3,4-dimethoxybenzoyl, 3,4,5-trimethoxy-

  benzyl, 1- (3-methoxyphenyl) ethyl, 2- (2-methoxyphenyl) ethyl,

  3- (2-ethoxyphenyl) propyl, 4- (4-ethoxyphenyl) butyl, 5- (3-ethoxy)

  phenyl) pentyl, 6- (4-isopropoxyphenyl) hexyl, 1,1-dimethyl-2- (4-

  hexyloxyphenyl) ethyl, 2-methyl-3- (3,4-dimethoxyphenyl) propyl,

  2- (3,4-dimethoxyphenyl) ethyl, 2- (3,4-diethoxyphenyl) ethyl, 2- (3,4,5-

  trimethoxyphenyl) ethyl, 1- (2,5-dimethoxyphenyl) ethyl, 3-nitro-

  benzyl, 1- (2-nitrophenyl) ethyl, 2- (4-nitrophenyl) ethyl, 3- (2,4-

  dinitrophenyl) propyl, 4- (2-aminophenyl) butyl, 5- (3-aminophenyl) -

  pentyl, 6 (4-aminophenyl) hexyl, 2,4-diaminobenzyl, 2-cyanobenzyl,

  1,1-dimethyl-2- (3-cyanophenyl) ethyl, 2-methyl-3- (4-cyanophenyl) -

  propyl, 2,4-dicyanobenzyl, 3,4-methylenedioxybenzyl, 3,4-

  ethylenedioxybenzyl, 2,3-methylenedioxybenzyl, 2- (3,4-methylene)

  phenyl) ethyl, 1- (3,4-ethylenedioxyphenyl) ethyl, 3-methyl-4-chloroethyl

  benzyl, 2-chloro-6-methylbenzyl, 2-methoxy-3-chlorobenzyl,

  2-hydroxybenzyl, 2- (3,4-dihydroxyphenyl) ethyl, 1- (3,4-dihydroxy)

  phenyl) ethyl, 2- (3-hydroxyphenyl) ethyl, 3- (4-hydroxyphenyl) -

  propyl, 6 (3,4-dihydroxyphenyl) hexyl, 3,4-dihydroxybenzyl,

  trihydroxybenzyl, 2-formylaminobenzyl, 3-acetylaminobenzyl, 3- (2-

  acetylaminophenyl) propyl, 4- (4-acetylaminophenyl) butyl, 2-propionyl-

  aminobenzyl, 3- (3-butyrylaminophenyl) propyl, 4- (4-isobutyrylamino)

  phenyl) butyl, 5- (2-tert-butylcarbonylaminophenyl) pentyl, 6 (3-

  pentanoylaminophenyl) hexyl, 2,4-diacylaminobenzyl, 4-methylthio-

  benzyl, 2- (2-methylthiophenyl) ethyl, 1- (3-methylthiophenyl) ethyl,

  3- (3-ethylthiophenyl) propyl, 4- (2-ethylthiophenyl) butyl, 5- (4-

  ethylthiophenyl) pentyl, 6 (3-isopropylthiophenyl) hexyl, 2-methyl-3- (4-hexylthiophenyl) propyl, 2- (3,4-dimethylthiophenyl) ethyl, 2- (2,5-dimethylthiophenyl) ethyl, 2- (3,4, 5-trimethylthioplyl) ethyl, 4acetyloxybenzyl, 3,4-acetyloxybenzyl, 3,4,5-triacetyloxybenzyl,

  1- (3-acetyloxyphenyl) ethyl, 2- (2-acetyloxyphenyl) ethyl, 3- (2-

  propionyloxyphenyl) propyl, 4- (4-pentanoyloxyphenyl) butyl, 5- (3-

  propionyloxyphenyl) pentyl, 6- (4-ixobutyryloxyphenyl) hexyl, 1,1-

  dimethyl-2- (4-hexanoyloxyphenyl) ethyl, 4-butyryloxybenzyl, etc. The term "lower alkanoylamino" means in

  the present description to designate an alkanoylamino group to

  straight or branched C1-C6 chain, such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, tert-butylcarbonylamino, hexanoylamino, etc. The term "lower alkylthio" means in the

  present description to designate an alkylthio group A chain

  straight or branched C1-Ce such as a methylthio, ethyl-

  thio, propylthio, isopropylthio, butylthio, tert-butylthio, pentyl-

  thio, hexylthio, etc. The term "lower alkanoyloxy" means in

  the present description to designate an alkanoyloxy group to

  straight or branched C1-C6 chain, such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tertbutylcarbonyloxy, hexanoyloxy, etc .; The term "lower phenylalkanoyl" means

  in the present description to denote a phenylalcano group.

  a ring having a C 1 -C 6 straight or branched chain alkanoyl group, such as a 2-phenylacetyl, 3-phenylpropionyl group,

  4-phenylbutyryl, 2-phenylbutyryl, 6-phenylhexanoyl, 2-phenyl-

  propionyl, 3-phenylbutyryl, 4-phenyl-3-methylbutyryl, 5-phenylbutyrate

  pentanoyl, 2-methyl-3-phenylpropionyl, etc. The term "lower phenylalkanoyl" substituted with 1 to 3 substituents selected from halogen atoms or lower alkoxy, lower alkyl, cyano, nitro, amino,

  hydroxy, lower alkanoylamino, lower alkylthio, and alkanoyl-

  lower oxy or lower alkylenedioxy group "means

  in the present description to denote a phenylalkyl group

  lower alkyl having 1 to 3 substituents selected from halogen atoms, and C1-C6 straight or branched chain alkoxy, C1-C6 straight or branched chain alkyl, no, nitro, amino, hydroxy, C1-C6 straight or branched chain alkanoylamino, C1-C6 straight chain or branched chain alkylthio and alkanoyioxy

  straight or branched chain C1-C6, or by a group aikylene-

  C1-C4 straight or branched chain dioxy, such as a 2-

  (2-chlorophenyl) acetyl, 2- (3-chlorophenyl) acetyl, 2- (4-chlorophenyl) -

  acetyl, 3- (2-fluorophenyl) propionyl, 4- (3-fluorophenyl) butyryl,

  2- (4-fluorophenyl) acetyl, 5- (2-bromophenyl) pentanoyl, 6- (3-bromo)

  phenyl) hexanoyl, 2-methyl-3- (4-bromophenyl) propionyl, 2- (3-iodo)

  phenyl) acetyl, 2. (4-iodophenyl) acetyl, 2- (3,5-dichlorophenyl) -

  acetyl, 2- (3,4-dichlorophenyl) acrylate, 3- (2,6-dichlorophenyl)

  pionyl, 4- (3,4-dichlorophenyl) butyryl, 2- (3,4-difluorophenyl) -

  acetyl, 5- (3,5-dibromophenyl) pentanoyl, 6 (3,4,5-trichlorophenyl) -

  hexanoyl, 2- (4-methylphenyl) acetyl, 2- (2-methylphenyl) acetyl,

  2- (3-methylphenyl) acetyl, 3- (3-ethylphenyl) propionyl, 4- (2-ethyl) -2-

  phenyl) butyryl, 5- (4-ethylphenyl) pentanoyl, - (3-isopropylphenyl) -

  hexanoyl, 2-methyl-3- (4-hexyl) propionyl, 2- (3,4-dinmethyl-phenyl) -

  acetyl, 2- (2,5-dimethylphenyl) acetyl, 2- (3,4,5-trimethylphenyl) -

  acetyl, 2- (4-methoxyphenyl) acetyl, 2- (3,4-dimethoxyphenyl) acetyl, 2- (3,4,5-trimethoxyphenyl) acetyl, 2- (3-methoxyphenyl) acetone. the,

  2- (2-methethoxyphenyl) acetyl, 3- (2-ethoxyphenyl) propionyl, 4- (4-

  ethoxyphenyl) butyryl, 5- (3-ethoxyphenyl) pentanoyl, 6- (4-isopropoxy)

  phenyl) hexanoyl, 2- (4-hexyloxyphenyl) acetyl, 2-methyl-3- (3,4-

  dimethoxyphenyl) propionyl, 2- (3,4-dimethoxyphenyl) acetyl, 2- (3,4-dimethylphenyl) propionyl

  diethoxyphenyl) acetyl, 2- (3,4,5-trimethoxyphenyl) acetyl, 2- (2,5-

  dimethoxyphenyl) acetyl, 2- (3-nitrophenyl) acetyl, 2- (2-nitrophenyl) -

  acetyl, 2- (4-nitrophenyl) acetyl, 3- (2,4-dinitrophenyl) propionyl,

  4- (2-Aminophenyl) butyryl, 5- (3-aminophenyl) pentanoyl, 6- (4-amino)

  phenyl) hexanoyl, 2- (2,4-diaminophenyl) acetyl, 2- (2-cyanophenyl) acetyl, 2- (3-cyanophenyl) acetyl, 2-methyl- (3- (4-cyanophenyl) propionyl, 2- ( 2,4-dicyanophenyl) acetyl, 2- (3,4-methylenedioxyphenyl) acetyl,

  2- (3,4-ethylenedioxyphenyl) -acetyl, 2- (2,3-methylenedioxyphenyl) -

  acetyl, 2- (3,4-methylenedioxyphenyl) acetyl, 2- (3,4-ethyl-

  dioxyphenyl) acetyl, 2- (3-methyl-4-chlorophenyl) acetyl, 2- (2-

  chloro-6-methylphenyl) acetyl, 2- (2-methoxy-3-chlorophenyl) acetyl,

  2- (2-hydroxyphenylacetyl, 2- (2,4-dihydroxyphenyl) acetyl, 2- (3-

  hydroxyphenyl) acetyl, 3- (4-hydroxyphenyl) propionyl, 6 {3,4-dihydroxy-

  phenyl) hexanoyl, 2- (3,4-dihydroxyphenyl) acetyl, 2- (3,4,5-tri-

  hydroxyphenyl) acetyl, 2- (2-formylaminophenyl) acetyl, 2- (3-ketyl) -

  aminophenyl) acetyl, 3- (2-acetylaminophenyl) propionyl, 4- (4-

  acetylaminophenyl) butyryl, 2 -, (2-propionylaminophenyl) acetyl,

  3- (3-Butyrylaminophenyl) propionyl, 4- (4-isobutyrylaminophenyl) -

  butyryl, 5- (2-tert-butylcarbonylaminophenyl) pentanoyl, 6- (3-

  pentanoylaminophenyl) hexanoyl, 2- (2,4-diacetylaminophenyl) acetyl, 2- (4-methylthiophenyl) acetyl, 2- (2-methylthiophenyl) acetyl, 2- (3-methylthiophenyl) acetyl, 3- (3-ethylthiophenyl) propionyl, 4- (2-ethylthiophenyl) butyryl, 5- (4-ethylthiophenyl) pentanoyl,

  6- (3-isopropylthiophenyl) hexanoyl, 2-methyl-3- (4-hexylthiophenyl) -

  propionyl, 2- (3,4-dimethylthiophenyl) acetyl, 2- (2,5-dimethylthio)

  phenyl) acetyl, 2- (3,4,5-trimethylphenyl) acetyl, 2- (4-acetyloxy)

  phenyl) acetyl, 2- (3,4-diacdtyloxyphenyl) acetyl, 2 <3,4,5-triacetyl-

  oxyphenyl) acetyl, 2- (3-acetyloxyphenyl) acetyl, 2- (2-acetyloxyphenyl) -

  acetyl, 3- (2-propionyloxyphenyl) propionyl, 4, - (4-pentanoyloxyphenantyl) -

  butyryl, 5- (3-propionyloxyphenyl) pentanoyl, 6- (4-isobutyryloxy)

  phenyl) hexanoyl, 2- (4-hexanoyloxyphenyl) acetyl, 2- (4-butyryloxy)

  phenyl) acetyl, etc. The compounds of the invention of formula (I) can be prepared by various methods. A preferred example is a process

  according to reaction scheme 1 below.

Reaction Scheme 1

N N-R3

NH2i3 to CH2CH2X

CH2CH2X

302.2 R1 R (II) (I)

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  In the formulas above, X represents a

  halogen atom, a lower alkanesulfonyloxy group, aryl-

1 2 3

  sulfonyloxy, arylalkylsulfonyloxy or hydroxy and R 1, R, R and the bond 34 of the carbostyril ring have the meanings defined above. In formula (III), examples of halogen atoms represented by X include chlorine, fluorine, bromine and iodine; examples of alcaiesulfonyloxy groups

  represented by X include the methanesulphonic groups

  fonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyl-

  oxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonylGxy, etc .; examples of the arylsulfonyloxy groups represented by X include substituted arylsulfonyloxy groups

* or not such as phenylsulfonyloxy, 4-methylphenylsulphonyl-

  oxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methethoxy

  phenylsulfonyloxy, 3-chlorophenylsulfonyloxy, α-naphthylsulfonyloxy, etc .; and examples of the arylalkylsulfonyloxy groups represented by X include substituted arylalkylsulfonyloxy groups or

  no, such as benzylsulfonyloxy, 2-phenylethylsulfonyl-

  oxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulphonyloxy, 2-methyl-

  benzylsulfonyloxy, 2-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyl-

  oxy, 3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy, etc. In the case where, among the compounds of formula (III), the starting materials are those in which X represents

  a halogen atom or a lower alkanesulfonyloxy group, aryl-

  sulfonyloxy or arylalkylsulfonyloxy, the reaction between the compound of formula (II) and the compound of formula (III) can be carried out generally in a suitable inert solvent, in the presence or in

  the absence of a basic condensing agent.

  Examples of suitable inert solvents which can be used include aromatic hydrocarbons, such as benzene, toluene, xylene, etc., lower alcohols, such as methanol, ethanol, isopropanol, butanol, etc., the acid acetic acid, ethyl acetate, dimethylsulfoxide, dimethylformamide, hexamethylphosphorotriamide, etc. Examples of basic condensation agents include carbonates, such as sodium carbonate, carbonate, and the like. potassium hydroxide, sodium bicarbonate, potassium bicarbonate, etc., metal hydroxides, such as sodium hydroxide, potassium hydroxide, etc., metal alkoxides, such as sodium methoxide, sodium ethoxide, etc., tertiary amines, such as pyridine, triethylamine, etc. In the above reaction, the proportion of the compound of formula (III) to the compound of formula (II) is not particularly

  limited and can be varied greatly. Ordinarily, we

  the reaction is killed by using at least an equimolar amount and preferably from 1 to 5 moles of the compound of formula (III) per mole of the compound of formula (II). The reaction may be carried out at about 40 to 120 ° C, preferably 50 ° to 100 ° C, and is usually completed in about 5 to 30 hours. On the other hand, in the case where one uses

  starting material of formula (III) a compound in which X represents

  a hydroxy group, the reaction between the compound of formula (II) and the compound of formula (III) can be carried out in the presence of a

  dehydrocondensation agent without solvent or in a suitable solvent

  prayed. Examples of dehydrocondensation agents include polyphosphoric acids, phosphoric acids such as orthophosphoric acid, pyrophosphoric acid, acid

  metaphosphoric, etc. Phosphorous acids, such as orthoacid

  phosphorous, etc., phosphoric anhydrides, such as pentoxide

  phosphorus, etc., inorganic acids, such as chlorinated

  water, sulfuric acid, boric acid, etc., metal phosphates, such as sodium phosphate, boron phosphate, ferric phosphate, aluminum phosphate, etc., activated alumina, sodium hydrogen sulfate, nickel Raney, etc. As solvents, high boiling solvents such as dimethylformamide, tetralin and the like can be used. In the above reaction, the proportion of the compound of formula (III) to the compound of formula (II) is not particularly limited and can vary widely. Ordinarily, the reaction is carried out with at least an equimolar amount and, preferably, from 1 to 2 moles of the compound of formula (III) per mole of the compound of

formula (II).

  The amount of the dehydrocondensation agent is not particularly limited and may vary widely. We

  usually uses at least a catalytic amount, preferably

  0.5 to 5 moles of the dehydrocondensation agent per mole of the compound of formula (II). Preferably, the above reaction is carried out in a stream of inert gas, such as carbon dioxide or nitrogen,

  to avoid the unwanted oxidation reaction.

  The reaction can be carried out either under atmospheric pressure or under higher pressure. Preferably, one performs

  the reaction under atmospheric pressure.

  The reaction can take place advantageously

  Preferably at about 100 to 350 C, preferably 125 to 255 C, and is generally complete in about 3 to 10 hours. Note that the compound of formula (III) can be

  used in the form of its pharmaceutically acceptable salt.

  Among the compounds of formula (1), those in which

  R represents a lower alkanoyl group or a phenylcarbonyl group;

  nyl or lower phenylalkanoyl which can bear on its

  1 to 3 substituents selected from halogen atoms,

  lower alkoxy, lower alkyl, cyano, nitro, amino, alkali

  lower alkylamino, lower alkylthio, lower alkanoyloxy and hydroxy, or lower alkylenedioxy group; an furoyl group, a pyridylcarbonyl group or a lower alkoxycarbonyl group; X

  represents a hydroxy group; R1, R and the 3-4 bond of the carbon nucleus

  styrile have the same meanings as above, may be

  patés according to reaction scheme 2 below.

Diagram 2

Y- "NH N / ---- NR3,

N NH 3 '1 N N-R 3'

I (V) I

  In the above formulas, R 1 represents a lower alkanoyl group, a phenylcarbonyl group or a lower phenylalkanoyl group which may bear on its benzene ring.

  1 to 3 substituents selected from halogen atoms and lower alkoxy, lower alkyl, cyano, nitr, amino, lower alkanoylamino, lower alkylthio, lower alkanoyloxy and hydroxy or lower alkylenedioxy groups; an furoyl, pyridylcarbonyl or lower alkoxycarbonyl group; X represents a hydroxy group; R1 and R2 and the 3-4 bond of the carbostyril ring have the

  same meanings as above.

  The process shown in Reaction Scheme 2

  above is a reaction between a carbostyril derivative of formula (IV) and a carboxylic acid of formula (V) using a conventional amide formation reaction. The process can be easily implemented

  by applying conditions of the known amidation reaction.

  Typical examples of the methods include:

(A) Mixed anhydride method.

  The compound of formula (V) is reacted with an alkyl haloformate to form its mixed anhydride which is

  is then reacted with an amine of formula (IV).

(B) "Activated ester" method.

  The carboxylic acid fomula (V) is converted into a "reactive ester" such as a p-nitrophenyl ester, an "ester" of N-hydroxysuccinimide, a "ester" of 1-hydroxybenzotriazole, etc.

  that is then reacted with an amine of formula (IV).

(C) Carbodiimide method.

  The carboxylic acid of formula (V) and an amine of formula (IV) are condensed in the presence of an activating agent, such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc.

(D) Other methods.

  The carboxylic acid of Formula (V) is converted to an acid anhydride using a dehydrating agent such as acetic anhydride, etc., and the product is reacted with an amine of formula (IV); process in which the lower alcohol ester of the carboxylic acid of formula (V) is reacted with an amine of formula (IV) at elevated temperature and under pressure; or the carboxylic acid of formula (V) is converted into an acid halide using a halogenating agent, and then

  react the product with an amine of formula (IV).

  In the mixed anhydride process, it is possible to

  mix the mixed anhydrides according to the classical SchottenBaumann reaction and then submit it without isolation to the reaction with

  the amine of formula (IV) to give the compound of formula (Ia).

  The Schotten-Baumarn reaction can be carried out in the presence of a basic compound. Any basic compounds conventionally used can be used as the basic compound.

  in the Schotten-Baumann reaction, for example organic bases

  such as triethylamine, trimethylamine, pyridine, N, N-dimethyl

  aniline, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonen-5 (DBN), 1,5diazabicyclo [5,4, undecene-5 (DBU), 1,4-diazabicyclo [2,2,2] octane (DABCO), etc., inorganic bases, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc. The reaction may proceed at about -20 ° C to about 0 ° C to about 50 ° C and continue for about 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the mixed anhydride and the amine of formula (IV) can be carried out at about -20 to 150 ° C, preferably at 50 ° C, for about 5 minutes to 10 hours, preferably 5 minutes to h. The mixed anhydride method can generally be carried out in a solvent. Any of the conventional solvents used in the mixed anhydride processes can be used, for example halogenated hydrocarbons, such as

  methylene chloride, chloroform, dichloroethane, etc., hydrochloride

  aromatic carbides, such as benzene, toluene, xylene, etc.,

  ethers, such as diethyl ether, tetrahydrofuran, dimethoxy

  ethane, etc., esters, such as methyl acetate, ethyl acetate, etc. and aprotic polar solvents, such as N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide, etc. Examples of suitable alkyl halogenoformates

  that can be used in the mixed mixed anhydride process

  take methyl chloroformate, methyl bromoformate,

  ethyl chloroformate, ethyl bromoformate, chloro

  isobutyl formate, etc. In the above reaction, one can ordinarily

  use the alkyl haloformate and the carboxylic acid of

  mule (V) in equimolar amounts relative to the amine of formula

  (IV). However, it is also possible to use 1 to 1.5 moles of the halogeno

  alkyl formate or carboxylic acid of formula (V) per mole

amine of formula (IV).

  On the other hand, the reaction between the carboxylic acid halide and the amine of formula (IV) can be carried out in a suitable solvent in the presence of a basic compound. Various known basic compounds can be used, for example sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like. in addition to the basic compounds used in the Schotten-Baumann reaction above. Examples of suitable solvents include, in addition to those used in the Schotten-Baumann reaction above, alcohols, such as methanol, ethanol,

  propanol, butanol, 3-methoxy-1-butanol, 2-ethoxyethanol, 2-methoxy-

  ethanol, etc. pyridine, acetone, and the like.

  The proportion of the carboxylic acid halide

  amine of formula (IV) is not limited and may vary widely.

  is lying. Ordinarily, at least 1 mole, preferably 1 mole, of the carboxylic acid halide per mole of the amine is used.

of formula (IV).

  The reaction may be carried out at -20 ° to 180 ° C., preferably at 0 ° to 150 ° C., and generally terminated in 5 minutes to 30 hours. Among the compounds of formula (I), those in which

  R3 represents a lower alkanesulfonyl group, (lower alkoxy) -

  lower carbonylalkyl, a phenylsulfonyl group which may be substituted on its benzene ring by a lower alkyl group; lower alkyl, lower alkenyl, lower alkynyl; or

  a lower phenylalkyl group which can carry on its benzene ring

  1 to 3 substituents selected from halogen atoms and lower alkoxy, lower alkyl, nitro, cyano, amino,

  a lower alkanoylamino group, lower alkylthio, alkanoyl-

  lower oxy or hydroxy or a lower alkylenedioxy group

  can be prepared according to Reaction Scheme 3 below.

Reaction Scheme 3

N N-R3

R3 "X2 (VI) R2

R} A N R2 O

  In the above formula, R 3 is a lower alkanesulfonyl group, a lower alkoxycarbonyl lower alkyl group, a phenylsulfonyl group which may be substituted on its own.

  benzene ring with a lower alkyl group; a lower alkyl group

  lower alkenyl, lower alkynyl, or a lower phenylarfl group which may have on its benzene ring 1 to 3 substituents selected from halogen atoms and lower alkoxy groups,

  lower alkyl, nitro, cyano, amino, lower alkanoyamino, alkyl

  lower thio, lower alkanoyloxy and hydroxy or an alkylene group

2 1 2 -

  lower dioxy, X represents a halogen atom, R R and the bond

  of the carbostyril nucleus have the same meanings as above.

  The reaction between the compound of formula (IV) and the compound of formula (VI) can be carried out under conditions similar to those used in the reaction between the compound

  of formula (IV) and the carboxylic acid halide above.

  Among the compounds of formula 1, those in which R 3 represents a lower (lower alkoxy) carbonylalkyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a lower phenylalkyl group which may bear on its benzene ring 1 to 3 substituents selected from

  halogen atoms, lower alkoxy groups, lower alkyl

  nitro, cyano, amino, lower alkanoylamino, lower alkylthio

  lower alkanoyloxy, and hydroxy or an alkylenedioxy group

  can be prepared according to the reaction scheme 4 below.

below. Reaction scheme 4

CH CH X

NH2 N - 2CH2CHX

X2CH2CH2X

(VII) _

1R'1 R

(II) (VIII)

3111 N-- R3 "'

NH 2 -R 3 N N-R

1 (IX) R (Ic)

1 0.

101 o

R '

  In the above formulas, R is a lower alkoxycarbonylalkyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a lower phenylalkyl group which may bear on its benzene ring 1 to 3

  substituents selected from lower alkoxy, lower alkyl,

  the halogen atoms, nitro, cyano, amino, alkanoyl-

  lower amino, lower alkylthio, lower alkanoyloxy, and

1 2 2

  hydroxy, or an alkylidenedioxy group and R, R $ 2, X, X and the linkage

  3-4 of the carbostyril ring have the same meanings as above.

  The reaction between the compound of formula (II) and the compound of formula (VII) can be carried out in the presence of a basic compound. As the basic compound, various known compounds can be used, for example inorganic salts, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate, and the like. alcoholates, such as sodium methoxide, sodium ethoxide, etc., organic bases, such as triethylamine, pyridine, N, N-dimethylaniline, etc. The reaction can take place either in the absence of solvent or in the presence of a solvent. Any inert solvents which have no effect can be used as the solvent.

harmful on the reaction.

  Examples of suitable inert solvents include

  take alcohols, such as methanol, ethanol, propanol, ethylene-

  glycol, etc., ethers, such as dimethyl ether, tetrahydrofuran, dioxantine, 2-dimethoxyethane, bis (2-methoxyethyl) ether, etc.,

  ketones, such as acetone, methyl ethyl ketone, etc., hydro-

  aromatic carbides, such as benzene, toluene, xylene, etc., esters, such as methyl acetate, ethyl acetate, etc.,

  aprotic polar solvents, such as N, N-dimethylformamide, dimethyl

  sulfoxide, hexamethylphosphorotriamide, etc. The reaction can be carried out advantageously

  in the presence of a metal iodide, such as potassium iodide.

  The proportion of the compound of formula (VII) to the compound of formula (II) is not particularly limited but may vary widely. It is preferred that the compound of formula (VII) is ordinarily used in a large excess when the reaction takes place without a solvent, and in an amount of 2 to 10 moles, preferably 2 to 4 moles, per mole of the compound of formula (II) . when the reaction

  is carried out in the presence of a solvent.

  The reaction temperature is not particularly

  However, the reaction is ordinarily carried out at about room temperature up to 200 ° C, preferably at 1600 ° C. Usually, the reaction settles for 1 to 30 hours. The reaction between the compound of formula (VIII) and the compound of formula (IX) can be carried out under conditions

  analogous to those of the reaction between compound (II) and compound (III).

  Among the compounds of formula (I), those in

  which R represents a lower (lower alkoxy) carbonylalkyl group

  lower alkyl, lower alkenyl, lower alkynyl, or lower phenylalkyl

  which may have on its benzene ring 1 to 3 substituents chosen

  among the halogen atoms and the lower alkoxy, lower alkyl, nitro, cyano, amino, lower alkanoylamino, lower alkylthio, lower alkanoyloxy and hydroxy or lower alkylenedioxy groups may also be prepared according to

  reaction scheme 5 below.

Reaction Scheme 5

-CH2CH2X

C2CH2X

(x,) (II) R N / AN 2 '1 y R (XI)

NH2-R3 '

  (IX) R ((Id) In the above formulas, R1, R2 R3, X and the 3-4 bond of the carbostyril ring have the same meanings

than above.

  The reaction between the compound of formula (II) and the compound of formula (X) can be carried out under conditions similar to that of the reaction between the compound of formula (II)

and the compound of formula (III).

  The reaction between the compound of formula (XI) and the compound of formula (IX) can be carried out either in the absence of solvent or in the presence of a suitable solvent using an acid. Examples of solvents that can be used include

  high-boiling solvents, such as tetralin, dimethyl-

  formamide, dimethylsulfoxide, hexamethylphosphorotriamide, etc. As the acid, it is possible to use hydrochloric acid, sulfuric acid, hydrobromic acid, etc. The proportion of the compound of formula (IX) to the compound of formula (XI) is not particularly limited and may vary widely. Ordinarily, at least 1 mole is used, preferably 1 mole

  to 2 moles, of the compound of formula (IX) per mole of the compound of formula (X).

  The reaction may be carried out at about 250 ° C, preferably 150 ° C to 200 ° C, and is generally complete in about 1 to 24 hours. In addition, the compounds of formula (I) can be

  prepared according to reaction scheme 6 below.

Reaction Scheme 6

CH CHX 3

R 4 R3N, 2 2

  R a> 2CHCHX RX o (III) ;. x 22 / (xII) (X II)

cyclisation -

  R (Ie) In the formulas above, R represents a

  halogen atom and R, R2, R3, X and the 3-4 bond of the carbon nucleus

  Styrile have the same meanings as above.

  The reaction between the compound of formula (XII) and the compound of formula (III) can be carried out under conditions similar to those used in the reaction between compound (II)

and the compound (III).

  The cyclization reaction of the compound (XIII), which

  is usually called Friedel Crafts reaction, can be done

  killed in a solvent in the presence of a Lewis acid.

  Those used conventionally in this type of reaction, for example disulfide, may be used as solvent.

  carbon, nitrobenzene, chlorobenzene, dichloromethane, dichloro-

  ethane, trichloroethane, tetrachloroethane, etc.

  In the above reaction, one can advantageously

  use any conventional Lewis acid, for example aluminum chloride, zinc chloride, ferrous chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, etc. The amount of Lewis acid used is not

  particularly limited, but may vary appropriately.

  Ordinarily, 2 to 6 moles, preferably 3 to 4 moles, are used.

  of Lewis acid per mole of the compound of formula (XIII).

  The reaction temperature may suitably vary, but is usually from about 20 to 120 ° C, preferably from 40 ° to 70 ° C. The reaction time depends on the starting materials, the catalysts, the reaction temperature, etc. and

  can not be established in a unique way. Ordinarily, the reaction

  This is complete in about 30 minutes to 6 hours. The compound of formula (I) can be prepared according to

  reaction scheme 7 below.

Reaction scheme 7

N N-R3 N <3

R12

N (XIV)

GOLD

R H R'1

  (If) ('g) In the above formulas, R 2, R 3, X and the 3-4 bond of the carbostyril ring have the same meanings as above, with the proviso that R 1 and R should not be

  simultaneously hydrogen atoms.

  The reaction between the compound (If) and the compound (XIV) can advantageously be carried out, for example, in a solvent

  suitable in the presence of a basic compound.

  As the basic compound, it is possible to use, for example, sodium hydride, metallic potassium, sodium metal, sodium amide, potassium amide and the like. Examples of solvents include ethers, such as dioxane, diethylene glycol dimethyl ether, etc., aromatic hydrocarbons, such as toluene, xylene, etc., aprotic polar solvents, such as

  dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide, etc.

  The proportion of compounds of formula (If) to compounds of formula (XIV) is not particularly limited and can be freely varied. At least 1 mole, preferably 1 to 2 moles, of the compound (XIV) is usually used per mole of

compound (If).

  The reaction may be carried out at about 0 ° to 70 ° C., preferably at room temperature, and generally complete in about 30 minutes to 12 hours.

  Among the compounds of formula (I), those in

  which the 3-4 bond of the carbostyril ring is a double bond (a single bond) can be prepared from the corresponding compounds in which this bond is a single bond

  (a double bond), according to reaction scheme 8 below.

  Reaction Scheme 8 _ \ -R3 / ÀNwR3 Dehydrogenation Reduction X N

R R '

  R (Ih). (Ii) -d 1 2 3 In the formulas above, R, R and R have the

same singifications as above.

  The reduction reaction of the compounds of formula (Ii) can be carried out under conventional conditions for catalytic reductions. Examples of catalysts that can be used include metals, such as palladium, palladium on carbon,

  tine, Raney nickel, etc., in the usual catalytic amounts

used.

  As a solvent, it is possible to use, for example, methanol, ethanol, isopropanol, dioxane, THF, hexane, cyclohexane, ethyl acetate, etc. The reduction reaction reaction can be carried out either under atmospheric pressure or under higher hydrogen pressure. Ordinarily, the reaction is carried out between atmospheric pressure and 20 bar, preferably between atmospheric pressure and 10 bar. The reaction temperature is usually

  from 0 to 150 ° C., preferably from room temperature to 100 ° C.

  The dehydrogenation reaction of the compound of

  mule (Ih) can be carried out in a suitable solvent using

  an oxidizing agent. Examples of suitable oxidizing agents include

  take benzoquinones, such as 2,3-dichloro-5,6-dicyanobenz

  quinone, chloranil (2,3,5,6-tetrachlorobenzoquinone), etc., halogenating agents, such as N-bromosuccinimide, N-chlorosuccinimide, bromine, etc. hydrogenation catalysts, such as selenium dioxide, palladium carbon, palladium black, vanadium oxide, Raney nickel, and the like. The amount of the oxidizing agent that is used is not particularly limited and can vary widely. 1 to 5 moles, preferably 1 to 2 moles, of the oxidizing agent are generally used per mole of the compound of formula (Ih). When hydrogenation catalysts are used, they are ordinarily used.

in catalytic amounts.

  Examples of suitable solvents include ethers, such as dioxane, THF, methoxyethanol, dimethoxyethane, etc., atomic hydrocarbons, such as benzene, toluene,

  xylene, cumene, etc., halogenated hydrocarbons, such as dichloro-

  methane, dichloroethane, chloroform, carbon tetrachloride, etc., alcohols, such as butanol, amyl alcohol, hexanol, etc., protic polar solvents, such as acetic acid, etc.,

  aprotic polar solvents, such as DMF, DMSO, hexamethylphosphoric acid,

  phorotriamide, etc. The reaction can be performed ordinarily

  between room temperature and 300 C, preferably temperature

  ambient temperature at 200 ° C., and is generally complete in about 1 to 40 hours.

  Among the compounds of formula (I), those in

  which R represents a hydrogen atom and the 3-4 bond of the carbostyril ring is a double bond can be in the form

  lactam-lacime tautomers, as shown below.

  % \ (Tij) N "NR3 R (Ik) In the formulas above, R and R have the same

  sitnifications only in the definitions as above.

  In addition, the compound of formula (I) can be

  also prepared according to reaction scheme 9 below.

Reaction scheme 9 -OR5

* (XIV ') (XV)

N N-R3

\\ / oR5

CR_ HOR5 '

R 2

IXVIII)

(XVI) Hydrolysis hydrolysis _R3

(XVII)

  (XIX) Reaction scheme 9 (continued)

N / ---- \ R3 --_ 3

N N-R3

COOH

CH HCHCOR6

CH2 CH = CHCOOH CH = CHCOR6

COOH

-N-- --4 N R

(XX) R2 2 * 2

(XXI) (XXII)

N N-R

> (I)

  Reduction CH ----- CHCOR hydrogenations |

2 N N-R

R C

(XXIIIa) CHCOR

R - NHR7

  (XXIIIb) In the above formulas, R2 and R have the same meanings as indicated above in the definitions, R5 and R5 each represent a lower alkyl group, or R5 and R5 taken together with the oxygen atoms to which they are bonded may be combined to form a lower alkylidenedioxy group, X represents a halogen atom, R represents a hydroxy group or a lower alkyl group, R6 represents a lower alkyl group and R7

  represents a lower alkanoyl group.

  Examples of halogen atoms represented by X

  include fluorine, chlorine, bromine and iodine.

  Examples of alkylenedioxy groups include methylenedioxy, ethylenedioxy, trimethylenedioxy, and the like. Of the compounds of formula (XV), some are new compounds and others are known compounds, which may be

  be prepared, for example, by nitration of the compounds of formula (XIV ').

  The nitration reaction of the compound of formula (XIV ') can be carried out under conditions similar to those used in conventional nitration reactions of aromatic compounds, for example using a nitrating agent, in particular

  the absence of solvent or in the presence of a suitable inert solvent.

  The inert solvent may be exemplified by, for example, acetic anhydride, concentrated sulfuric acid, and the like. and the nitrating agent, for example, with acids, such as fuming nitric acid, concentrated nitric acid, mixed acid (mixture of nitric acid with sulfuric acid, sulfuric acid

  fuming, phosphoric acid or acetic anhydride), a combination of

  sulfuric acid and alkali metal nitrates, such as potassium nitrate, sodium nitrate, etc. The amount of the nitrating agent to be used is usually at least an equimolar amount, preferably an excess relative to the starting compound, and the reaction can be conveniently carried out between about 0 ° C and room temperature for 1 to 4 hours. The acetalization of the formyl group in the compound of formula (XV) can be carried out in a suitable solvent in the presence of an acetalizing agent and an acid. In the action, any solvents that do not harm the

  reaction. For example, aromatic hydrocarbons can be used.

  such as benzene, toluene, xylene, etc., alcohols, such as

  methanol, ethanol, etc., dinmethylformamide, dimethyl-

  sulfoxide, etc. Examples of acetalizing agents include alcohols, such as methanol, ethanol, isopropanol ethylene glycol, etc., carboxylic acid orthoesters, such as ethyl orthoformate, etc. Examples of acids include, for example, mineral acids, such as hydrochloric acid, sulfuric acid, etc., organic acids, such as p-toluenesulfonic acid, and the like. The amount of acetalizing agent to be used is at least 1 mole, preferably 1 to 1.5 mole, of the agent

  acetalization per mole of the compound of formula (XV) when

  reads carboxylic acid orthoesters. On the other hand, when using alcohols, at least 2 moles are used, usually

  a large excess of the acetalizing agent per mole of the compound of

mule (XV).

  The reaction can be carried out usually at a temperature of from 0 to 50 ° C, preferably at about room temperature, and is complete in about 30 minutes to 5 hours. The reaction between the compounds of formula (XVI) and the compound of formula (XVII) can be carried out in the presence of a

  solvent. As a solvent, for example, hydrocarbons can be

  aromatics, such as benzene, toluene, xylene, etc., lower alcohols, such as methanol, ethanol, isopropanol, etc., ethers, such as dioxane, tetrahydrofuran, dimethoxyethane,

  diethyl ether, etc., polar solvents, such as N-methyl-

  pyrrolidone, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid,

  phorotriamide, etc. More preferably, the reaction may be carried out using a basic compound as an acid acceptor. Examples of basic compounds include potassium carbonate, sodium carbonate, sodium hydride, sodium bicarbonate, sodium amide, sodium hydroxide, tertiary amines, such as triethylamine, tripropylamine, etc. ., the

  pyridine, quinoline and the like.

  In the above reaction, a suitable amount

  the piperazine derivative of formula (XVII) to be used is ordinarily

  from 1 to 10 moles, preferably 3 to 7 moles, of the compound (XVII)

per mole of the compound (XVI).

  The reaction may be carried out at 50 to 150 ° C, preferably at 50 to 100 ° C, and is generally complete in about 1 hour 30 minutes to 10 hours. The hydrolysis reaction of the compound of formula (XVIII)

  can be carried out in an alcohol, such as methanol, ethanol, iso-

  propanol etc., using a mineral acid such as chloroacid

  water, sulfuric acid, etc., at a reaction temperature between room temperature and the boiling point of the solvent to be used, for 30 minutes to 3 hours. The reaction between the compound of formula (XIX) and the malonic acid of formula (XX) can be carried out in a suitable solvent, in the presence of a basic compound. As the solvent, any of the solvents which can be used in the reaction between the compound of formula (XVI) and the compound of formula (XVII) can be used. In addition, it is also possible to use solvents

polar, such as pyridine.

  Examples of suitable basic compounds include potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, tertiary amines, such as triethylamine, tripropylamine, piperidine, etc. pyridine,

quinoline and analogues.

  In the above reaction, a suitable amount of the malonic acid of formula (XX) is at least an equimolar amount.

  preferably 2 to 7 moles, of the compound of formula (XX)

mole of the compound of formula (XIX).

  The reaction can usually be

  0 to 200 ° C., preferably 70 ° to 150 ° C., and is generally finished.

  in about 1 to 10 hours. The esterification reaction of the compound of formula (XXI) can be carried out in an alcohol, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and the like. in the presence of an acid, such as hydrochloric acid, sulfuric acid, etc. or a halogenating agent, such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, etc., at a reaction temperature of about 0 to 150 ° C, preferably 50 ° C, for about 1 hour. at 10 o 'clock. In the above reaction, a suitable amount of the acid to be used is usually 1 to 1.2 moles relative to the compound of formula (XXI) and the amount of the halogenating agent to be used is at least an equimolar amount, preferably

  1 to 5 moles, of the halogenating agent per mole of the compound of formula (XXI).

  The reduction reaction of the compounds of formula (XXI) and formula (XXII) can be carried out either (1) by carrying out the reduction in a suitable solvent and using a catalyst for the catalytic reduction, or (2) by carrying out the reduction. using a reducing agent such as a mixture of a metal or a metal salt and an acid, a mixture of a metal or a metal salt and an alkali metal hydroxide, sulphate,

  or an ammonium salt, and the like.

  When using the catalytic reduction (1), examples of solvents that can be used include water

  acetic acid, the alcoholstels that methanol, ethanol, isopropyl

  etc., hydrocarbons, such as hexane, cyclohexane, etc., ethers, such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, etc., esters, such as ethyl acetate, methyl acetate, etc., aprotic polar solvents, such as N, N-dimethylformamide, etc. As catalysts, it is possible to use palladium, palladium black, palladium-on-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and the like. A suitable amount of the catalyst to be used is 0.02 to 1.00 parts by weight per part by weight

  of the compound of formula (XXI) or (XXII). The reaction can be done

  It is heated from about -20 ° C to room temperature, preferably from 0 ° C to room temperature, under a hydrogen pressure of 1 to 10 bar, for about 30 minutes to 10 hours.

  On the other hand, when using the reaction (2)

  The reducing agent used is a mixture of iron, zinc, tin or stannous chloride and a mineral acid, such as hydrochloric acid, sulfuric acid, etc. or a mixture of iron, ferrous sulphate, zinc or tin and an alkali metal hydroxide, such as sodium hydroxide, etc., sulphates,

  such as ammonium sulphate, etc., ammonia or an ammonium salt

  such as ammonium chloride, etc. Examples of suitable inert solvents that may be used include water, acetic acid, methanol, ethanol, dioxane, and the like.

  The conditions for the reduction reaction

  may be chosen in a suitable manner, depending on the reducing agent to be used. For example, when a mixture of stannous chloride and hydrochloric acid is used as the reducing agent, the reaction can be carried out advantageously between about 0 ° C. and room temperature for about 30 minutes to 10 hours. A suitable amount of the reducing agent is an at least equimolar amount, preferably 1 to 5 moles, of the reducing agent per

mole of the starting compound.

24933i0

  In addition, when using the reaction (1)

  above, preferably at 50 to 150C, the compound of formula (I) can be obtained by direct cyclization without isolation of the compound of

formula (XXIIIa) or (XXIlIb).

  The acylation reaction of the compound of formula (XXIIIa) can be carried out under conditions analogous to those in which the compounds of formula (I) in which R3 represents a (lower alkanoyl) aminobenzoyl group can be prepared,

as described below.

  The cyclization reaction of the compound of formula (XXIIIa) or (XXIIIb) to form the compound of formula (I) can be carried out in a suitable solvent in the absence or presence of a

  basic compound or an acid, preferably in the presence of an acid.

  Examples of suitable basic compounds include

  take organic bases, such as triethylamine, trimethyl-

  amine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diaza-

  bicyclo [4.3.0] nonene-5 (DBN), 1,5-diazabicyclo [5.4.0] undecene-5 (DBU), 1,4-diazabicyclo [2,2,2] octane (DABCO) etc., inorganic bases, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. Examples of suitable acids include hydrochloric acid, sulfuric acid, polyphosphoric acid, and the like.

  Any solvents can be used as the solvent.

  which do not interfere with the reaction. Examples of solvents

  such as alcohol, methanol, ethanol,

  panol, butanol, 3-methoxy-1-butanol, 2-ethoxyethanol, 2-methoxyethanol, etc., pyridine, acetone, halogenated hydrocarbons, such as

  methylene chloride, chloroform, chloroethane, etc., hydrocarbons

  aromatic compounds, such as benzene, toluene, xylene, etc., ethers, such as diethyl ether, tetrahydrofuran, dimethoxyethane, etc., esters such as methyl acetate, ethyl acetate, etc., and solvents. aprotic polar, such as N, N-dimethylformamide,

  dimethylsulfoxide, hexamethylphosphorotriamide, etc., and mixtures thereof.

  The reaction can usually be from -20

  at 150 ° C., preferably between 0 ° C. and 1500 ° C., and is generally finished.

between 5 min and 30 h.

  Among the compounds of formula (If) according to the invention

  those in which R is phenylcarbonyl, lower phenylalkyl, or lower phenylalkanoyl, each having on its benzene ring 1 to 3 amino groups can be readily prepared by reduction of a corresponding compound wherein R 3 is phenylcarbonyl phenyl-lower alkyl, phenyl-lower alkanoyl, each having on its benzene ring 1 to 3 nitro groups. This reduction reaction may be carried out analogously to conventional reactions in which an aromatic nitro compound is reduced to the corresponding aromatic amino compound. More particularly, a process may be used in which a reducing agent such as sodium nitrite, sulfurous gas, etc. is used, a catalytic reduction process using a

  reduction catalyst, such as palladium-carbon, etc., and

gists.

  Among the compounds of formula (I), those in

  which R represents a hydrogen atom can also be

  prepared by subjecting the decomposition of ether to a corresponding compound.

  compound of formula (I) in which R represents an alkoxy group

  inferior. The decomposition of the ether can be carried out in

  the presence of a Lewis acid, for example boron tribromide, tri-

  boron fluoride, aluminum chloride, etc., ordinarily

  excess relative to the starting compound at an ordinary temperature

  between about -30 ° C. and the ambient temperature.

  Among the compounds of formula (I), those in which

  R3 represents a phenylcarbonyl group, a lower phenylalkyl group,

  or a lower phenylalkanoyl group, each substituted on its benzene ring by 1 to 3 substituents selected from lower alkanoylamino groups and lower alkanoyloxy groups, may be prepared by acylation of a corresponding compound of formula (I) wherein R represents a phenylcarbonyl group,

  a lower phenylalkyl group or a lower phenylalkanoyl group

  each substituted on its benzene ring by A3 substituted

  selected from amino groups and hydroxy groups.

  Examples of acylating agents include, for example, lower alkanoic acids, such as acetic acid, etc., lower alkanoic acid anhydrides, such as acetic anhydride, etc., lower alkali acid halides, such as acetyl chloride, etc. When an anhydride or a lower alkanoic acid halide is used as the acylating agent, the acylation reaction is

  It can be used in the presence of a basic compound.

  Examples of basic compounds are, for example, alkali metals, such as sodium metal, potassium metal, etc., their hydroxides, carbonates and bicarbonates, aromatic amines, such as pyridine, piperidine, etc. The reaction can proceed either in the absence of solvent or in the presence of a solvent. Ordinarily, it can be carried out in a suitable solvent. Examples of solvents are ketones, such as acetone, methyl ethyl ketone, etc.

  ethers, such as diethyl ether, dioxane, etc., hydro-

  aromatic carbides, such as benzene, toluene, xylene, etc., water

and analogues.

  A suitable amount of acylating agent to be used varies between an equimolar amount and a high excess, preferably

  between 5 and 10 moles of the acylating agent per mole of the starting compound.

  The reaction can take place between 0 and 150 C,

preferably from 0 to 80 C.

  When using such an acylating agent as an alkaline

  In a lower reaction, the reaction may advantageously take place in the presence of a dehydrating agent, for example mineral acids, such as sulfuric acid, hydrochloric acid, etc.,

  sulfonic acid, such as p-toluenesulfonic acid, benzene

  sulfonic acid, ethanesulfonic acid, etc., the reaction temperature

  being maintained preferably between 50 and 120C.

  Among the compounds of formula (I), those in which

  R3 represents a phenylcarbonyl group, a lower phenylalkyl group,

  or a lower phenylalkanoyl group, each of which is substituted on its benzene ring by 1 to 3 substituents selected from hydroxy and amino groups, can be prepared by hydrolysis of a corresponding compound of formula (I) wherein R represents a phenylcarbonyl group, a lower phenylalkyl group or a lower phenylalkanoyl group, each of which is substituted on its benzene ring by 1 to 3 substituents selected from groups

  lower alkanoylamino and lower alkanoyloxy groups.

  The hydrolysis reaction can be carried out in a

  suitable solvent in the presence of an acid or a basic compound.

  Examples of solvents are, for example, water, lower alcohols, such as methanol, ethanol, isopropanol, etc., ethers, such as dioxane, tetrahydrofuran, etc., and mixtures thereof. Examples of suitable acids include mineral acids, such as hydrochloric acid, sulfuric acid,

  hydrobromic acid, etc., and examples of suitable basic compounds

  These include metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like. The reaction may advantageously be carried out at ambient temperature of 150 ° C., preferably at 80 ° C. to 120 ° C., and may be terminated in about 1 to 15 hours in general. The compounds of formula (I) may also be prepared according to reaction scheme 10 below.

N <-R3 R3 N <-R3

\ / \ R R

A-COOH

(XXV) Cyclisation

R R1 R O

  R (XXIV) (XXVI) (1h) In the formulas above, R, R and R have the same meanings as defined above, A represents a group of formula R CH = CH- in which R7 represents a lower alkoxy group or a halogen atom, a group of formula R80

CH-CH2-

  wherein R and R each represent a lower alkyl group

laughter, or a CHR-C- group.

  The compound of formula (XXIV) and the compound of formula

  mule (XXV) are known compounds and their reaction can be carried out analogously to the reaction between the compounds (IV)

and (V) previously described.

  The cyclization reaction of the aniline derivative of formula (XXVI) can be carried out in the presence of a solvent-free acid or in a suitable solvent. Acid is not particularly limited

  and a wide variety of inorganic and organic acids can be used.

  commonly used drugs; more particularly, one can use

  inorganic acids, such as hydrochloric acid, brominated acid,

  water, sulfuric acid, etc., Lewis acids, such as aluminum chloride, boron trifluoride, titanium tetrachloride, etc., organic acids, such as formic acid, acetic acid, ethanesulfonic acid, p-acid, toluenesulphonic, etc. Among these acids, hydrochloric acid, hydrobromic acid, and

sulfuric acid.

  The amount of acid to be used is not particularly

  limited and can be chosen in a suitable way -

  in a wide range. At least an equimolar amount, preferably 10 to 50 parts by weight of the acid, is usually used.

  per part by weight of the compound of formula (XXVI).

  Any conventional inert solvents can be used as the solvent. Examples of suitable solvents include water, lower alcohols, such as methanol, ethanol, propanol, etc., ethers, such as dioxane, tetrahydrofuran, aromatic hydrocarbons, such as benzene, toluene, etc., hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, etc., acetone, dimethylsulfoxide,

  dimethylformamide, hexamethylphosphorotriamide, etc. Among them-

  hereinafter water soluble solvents such as alcohols are preferred.

  ethers, acetone, dimethylsulfoxide, dimethyl-

  formamide, hexamethylphosphotriamide, etc. The above reaction can be carried out between 0 and C, preferably between room temperature and 60C, and can usually be completed in about 5 minutes to 6 hours. In addition, the compounds of formula (I) can be

  prepared according to reaction scheme 11 below.

  Reaction Scheme 11 -x 2 H \, / RN - X2

(XXVIII) I

  R

(XXVII) (1)

  In the formulas above, R, R2, R3 and X have

  the same meanings as defined above.

  The reaction between the compounds of formula (XXVII) and the compound of formula (XXVIII) can be carried out in a suitable inert solvent with or without the addition of a basic condensing agent. As examples of inert solvents, mention may be made, for example, of aromatic hydrocarbons, such as benzene, toluene, xylene, etc., alcohols, such as methanol, ethanol,

  propanol, butanol, 3-methoxy-1-butanol, 2-ethoxyethanol, 2-methoxy-

  ethanol, etc., pyridine, acetone, dimethylsulfoxide, dimethylfor-

  mamide, hexamethylphosphorotriamide, etc.

  Examples of basic condensation agents suitable for

  include sodium carbonate, potassium carbonate,

  sium, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, triethylamine, etc. The proportion of the compound of formula (XXVIII) to the compound of formula (XXVII) is not particularly limited and may vary

  widely. An amount usually at least equi-

  molar, preferably 1 to 5 moles, of the compound of formula (XXVIII)

  per mole of the compound of formula (XXVII).

  The reaction can be carried out usually from about room temperature to about 180 ° C, preferably from about 100 ° C to about 150 ° C, and is generally complete in about 3 to 30 hours. The reaction can be carried out advantageously in the presence of powder

copper as a catalyst.

  Among the compounds of formula (II), those in

  which an amino group is present in position 8 may also

  prepared according to reaction scheme 12 below. Reaction scheme 12

(XXIX)

NHR10 2) 2 (XXx) ORil XOR

(XXXI)

OR1l

(N II)

NOT

NHR10 H

(XXXII)

I H

? {R1O1 R1 H NHR

(XXXIV)

(XXVIII ')

(XXXMIII)

  (IIa) (IIb) In the above formulas, R0 is lower alkanoyl, R1 is lower alkyl and X2

a halogen atom.

  The acylation reaction of the compound of formula (XXVII) can be carried out analogously to the acylation reaction.

  of the compound of formula (XXIIIa) above.

  The reduction reaction of the nitro group in the compound of formula (XXIX) can be carried out analogously to the reduction reaction of the compound of formula (XXI)

or (XXII).

  The reaction between the compound of formula (XXX) and the compound of formula (XXXI) can be carried out under conditions analogous to those of the reaction of the compound of

  formula (IV) with the compound of formula (V), except that the conditions

  reactions in the use of the carboxylic acid halide.

  Boxylic as compound (V) and its proportion to use are different. Although this reaction can be carried out

  the absence of basic compounds, it can take place advantageously

  with at least one equimolar amount, preferably 1 to 5 moles, of the compound of formula (XXX) per mole of the

formula (XXXI).

  The cyclization reaction of the compound of

  mule (XXXII) may be carried out under conditions similar to

  those of the cyclization reaction of the compound of formula (XXVI).

  The reduction reaction of the carbostyril derivative of formula (XXXIII) can be carried out analogously to

  the reduction reaction of the carbostyril derivative of formula (Ii).

  The hydrolysis reaction of the carbostyril derivative

  of formula (XXXIII) or (XXXIV) can be performed in a

  to the reduction reaction of the compound of formula (I) in

  wherein R represents a lower alkanoylamino benzoyl group.

  The compounds of the invention represented by formula (I) prepared as described above can form pharmaceutically acceptable salts and the invention is also directed to those pharmaceutically acceptable salts. The pharmaceutically acceptable acids that can be used for salification can be various

  inorganic acids, for example hydrochloric acid, sulphuric acid

  phosphoric acid, hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid and the like.

like.

  The compounds of formula (1) can be converted into a corresponding salt when they carry an acid group by reaction of the acid group with a basic compound acceptable in the pharmacy. Examples of basic compounds are inorganic basic compounds, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, bicarbonate

of potassium, and the like.

  The compounds of formula (1) and their salts, obtained as described above, can be isolated from the respective reaction mixtures when the reaction is complete and purified by conventional techniques, for example by solvent extraction,

  dilution method, precipitation, recrystallization, chromatogra-

  column chromatography, preparative thin layer chromatography,

and analogues.

  As is obvious to those skilled in the art, the compounds of formula (I) may exist in optically

  these optical isomers form part of the invention.

  In the use of the compounds of the invention, of formula (I), and of their salts as therapeutic agents, these

  compounds can be incorporated into pharmaceutical compositions.

* ticks with acceptable pharmacy supports. Suitable carriers which may be used are, for example, solvents or excipients, such as fillers, diluents, binders, wetting agents, disintegrants, surfactants, and lubricants, which are ordinarily used to prepare these materials.

  drugs, depending on the type of dosage form.

  Various dosage forms of therapeutic agents as cardiotonic agents may be selected depending on the purpose of the therapy. Typical dosage forms that can be used are tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories

  and injectable preparations (solutions, suspensions, etc.).

  In the tabletting of a phar-a-

  The compounds containing the compounds of the formula (I) or their pharmaceutically acceptable salts as active ingredients can be used in a wide variety of carriers known in the art. Examples of suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, binders, such as water, ethanol, propanol , simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose,

  shellac, methylcellulose, potassium phosphate and polyvinyl

  pyrrolidone, disintegrants, such as dried starch, sodium alginate, agar powder, laminar powder, sodium bicarbonate, calcium carbonate, Tween ", sodium lauryl sulfate, monoglycerides

  stearic acid, starch and lactose, the inhibitors of

  such as white sugar, stearic acid glyceryl ester, cocoa butter and hydrogenated oils, absorption enhancers, such as quaternary ammonium bases and sodium lauryl sulphate, humectants, such as glycerol and starch, adsorbents, such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants, such as purified talc, stearic acid salts, boric acid powder, "Macrogol" (polyethylene glycol manufactured

  by Shinetsu Chemical Industry Co., Ltd.) and polyethylene

solid glycol.

  Tablets, if desired, can be coated

  and in the form of sugar-coated tablets, coated tablets

  gelatin tablets, enteric-coated tablets, film-coated tablets or tablets with two or more

layers.

  In putting in pills the phar-

  In the art, a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers are excipients, such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin and tale, the

  binders, such as gum arabic powder, gum powder,

  gloves, gelatin and ethanol and disintegrants, such as laminar and agar; In molding the pharmaceutical composition in the form of suppositories, a wide variety of

  carriers known in the art. Examples of suitable media

  polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin

  and semi-synthetic glycerides.

  When the pharmaceutical composition is put into the form of an injectable preparation, the

  solution or the resulting suspension and make it isotonic vis-

  with blood. In the preparation of a pharmaceutical composition in the form of a solution or suspension, any diluent usually used in the art can be used. Examples

  suitable diluents are water, ethyl alcohol,

  pylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene

  sorbitol and sorbitan esters. A therapeutic agent, such as a nephrite treating agent, sodium chloride, glucose or glycerol may be included in sufficient quantity to prepare isotonic solutions. The therapeutic agent may further contain the dissolution aids, buffers, pain relievers and ordinary preservatives.

  and, optionally, coloring agents, perfumes, flavorings, sweeteners,

corants and other medicines.

  The amount of the compound of formula (I) according to the invention and its pharmaceutically acceptable salts as an active ingredient to

  incorporate into a pharmaceutical composition useful as stimulator

  Cardiac heart is not particularly limited and may vary in a wide range. A suitable therapeutically effective amount of the compound of general formula (I) of the invention and its pharmaceutically acceptable salts is ordinarily from about 1 to 70% by weight, preferably 1 to 305% by weight, based on

the total composition.

  There is no particular limitation as to

  how to use the cardiotonic agent and it can be administered

  the appropriate channels for this. particular forms.

  For example, tablets, pills, liquid preparations, sus-

  Pensions, emulsions, granules and capsules can be administered orally. Injectable preparations are administered intravenously either alone or in admixture with ordinary auxiliary agents, such as glucose and amino acids. In addition, if necessary, the cardiotonic agent can be administered in isolation

  intramuscularly, intracutaneously, subcutaneously or intraperitoneally

  tonéale. Suppositories are administered intrarectally

  and the ointment is applied to the skin.

  The dose of the cardiotonic agent is chosen

  depending on usage, symptoms, etc. Ordinarily, a preferred dose of the compound of the invention is about 0, there 10 mg / kg body weight, per day. It is advantageous that the active ingredient is contained in a single unit dosage form in a quantity

from 2 to 200 mg.

  The following examples illustrate the invention without

however, limit its scope.

REFERENCE EXAMPLE 1

  29.3 ml of concentrated nitric acid are added dropwise to 500 ml of concentrated sulfuric acid while stirring and cooling with ice. In addition, we add drop by drop

  to the resulting mixture at 50C or less, 50 g of m-chlorobenzaldehyde.

  After stirring at room temperature for 1 hour, the reaction mixture is poured on ice to precipitate the solid which is collected by filtration. After washing with water, the solid thus obtained is dissolved in methylene chloride and the organic layer is washed with dilute aqueous sodium hydroxide, washed with water and dried over sodium sulfate. The Li-

  Distillation of the solvent gives 62.3 g of 2-nitro-5-

chlorobenzaldehyde, 65-690C.

REFERENCE EXAMPLE 2

  100 g of 2-nitro-5-chlorobenzaldehyde are dissolved in 1000 l of toluene and then added to the resulting solution

  p-toluenesulfonic acid and 87.8 g of ethyl orthoformate.

  The mixture is stirred at room temperature for 1 hour and

  neutralize the reaction mixture with a diluted solution of

  aqueous sodium hydroxide. After washing with water, the toluene layer is dried over anhydrous sodium sulphate and concentrated to obtain 138 g of 2-nitro-5-chlorobenzaldehyde diethyl acetal.

in the form of an oily product.

REFERENCE EXAMPLE 3

  138 g of nitro-5-chloroethyl diethylacetal are dissolved

  benzaldehyde in 750 ml of dimethylformamide (DMF) and 250 g of anhydrous piperazine are added to the solution and the mixture is stirred at 80 ° C. for 4 hours. After removal of the excess piperazine and DMF by evaporation under reduced pressure, the residue is added to the residue.

  a dilute aqueous solution of sodium hydroxide to dissolve it.

  The solution is then extracted with methylene chloride. The methylene chloride layer is washed with water and dried

  on sodium sulphate and then the solvent is distilled off

  tion. 850 ml of isopropyl alcohol are added to the residue in order to dissolve it and 65 ml of hydrochloric acid are added to the solution.

  concentrated and refluxed for 1 h. After cooling

  The crystals precipitating are collected by filtration.

  to obtain 93 g of 2-nitro-5-piperazinylbenzal hydrochloride

dehyde; F. 195-201 C.

REFERENCE EXAMPLE 4

  47 g of 2-nitro-5-piper hydrochloride are dissolved

  razinylbenzaldehyde in 500 ml of pyridine and 5 g of piperidine and 100 g of malonic acid are added to the solution, followed by refluxing for 5 h. After cooling, the crystals which form to obtain 42 g are collected by filtration.

  2-nitro-5-piperazinylcinnamic acid, mp 229-237 ° C.

REFERENCE EXAMPLE 5

  10 g of 2-nitro-5-piperanic acid are suspended.

  zinylcinnamic in 100 ml of ethyl alcohol and added drop

  dropwise to the suspension 3 ml of thionyl chloride while cooling

  both in the ice bath and shaking. When the bill is over,

  the mixture is refluxed for 3 hours and discarded by distillation.

  tillation ethyl alcohol and thionyl chloride. We add

  isopropyl alcohol to the residue and heated to dissolve it.

  After cooling, the crystals are collected by filtration

  yellow precipitates to obtain 4.3 g of 2-nitrohydrochloride

  ethylpiperazinylcinnamate; F. 210-220 C.

REFERENCE EXAMPLE 6

  5 g of 2-nitro-5-piperazinyl are suspended

  benzaldehyde in 50 ml of DMF and 6 ml of

  triethylamine. It is added dropwise with stirring and cooling.

  in a bath of ice, a solution of 4.4 g of

  dimethoxybenzoyl in 20 ml of DMF, and the mixture is stirred at room temperature for 2 h, then poured into saturated sodium chloride solution and extracted with sodium chloride.

  methylene. After washing with water, the chloromethylated layer is dried

  on anhydrous sodium sulphate. The solvent is then distilled off and methyl alcohol is added to the residue and the mixture is heated and cooled and recrystallized.

  crystals formed in DMF to give 4.5 g of 2-nitro-5- [4- (3,4-

  dimethoxybenzoyl-the-p4prazinyl] benzaldehyde; F. 196-198 C, in the form

yellow crystals.

REFERENCE EXAMPLE 7

  4 g of 2-nitro-5- [4- (3,4-dimethoxybenzoyl) -1 are dissolved

  piperazinylbenzaldehyde in 20 ml of pyridine, then 2.1 g of malonic acid and 0.4 ml of piperidine are added, and the mixture is stirred at 80 ° C. for 4 hours. After evaporation of pyridine and piperidine, the reaction mixture is poured into a dilute aqueous solution of hydrochloric acid and extracted with methylene chloride. After washing the chloromethylenic layer with water, the solvent is distilled off and methanol is added to the mixture.

  residue. After cooling, the crystals are collected by filtration.

  formed to obtain 3.7 g of 2-nitro-5- [4- (3,4-dimethoxy)

  benzoyl) -l-piperazinyl] cinnamic; F. 197-202 C.

REFERENCE EXAMPLE 8

  12 g of 2-nitro-5- [4- (3,4-dihydrogen)

  methoxybenzoyl) -1-piperazinyl] cinnamic in 60 ml of acid

  hydrochloric acid and add dropwise to the solution.

  resultant solution of 20 g of stannous chloride in

  ml of concentrated hydrochloric acid at room temperature.

  After stirring for 2 h, the precipitated crystals are collected by filtration. The crystals thus obtained are dissolved in 240 ml of methanol and the solution is neutralized with a 10% aqueous solution of sodium hydroxide to precipitate crystals which are then collected by filtration. After concentration of the methanolic solution, the mixture is recrystallized

  residue in ethanol to obtain 6.3 g of 2-amino-5- [4-

  (3,4-dimethoxybenzoyl) -l-piperazinyl] cinnamic.

Mp 168-170 ° C, pale yellow powder.

REFERENCE EXAMPLE 9

  5 g of 2-amino-5- [4- (3,4-dihydrogen)

  methoxybenzoyl) -1-piperazinyl] cinnamic in a solvent mixture

  consisting of ethanol and water. After adding 0.5 g of char-

  good palladium at 5%, the mixture is reduced by hydrogen under

  atmospheric pressure. After absorption of the theo-

  In the presence of hydrogen, the catalyst is filtered off and the hydroethanol phase is concentrated to dryness. The residue is dissolved in chloroform and separated by chromatography.

  on a column of silica gel to obtain 1.5 g of 3- [2-

  amino-5- {4- (3,4-dimethoxybenzoyl) -1-piperazinyl) phenyl] propionic acid

Picnic.

F. 98-101 C.

REFERENCE EXAMPLE 10

  4.4 g of 3- [2-amino-5-t4-acid are dissolved

  (3,4-dimethoxybenzoyl) 1-piperazinylphenyl] propionic acid in ml of acetic acid. 1.1 g of acetic anhydride are added to this solution and the mixture is stirred for 1 hour at room temperature. After concentrating the acetic acid, water is added to the reaction mixture. The precipitated crystals are collected by filtration, washed with water and recrystallized from a solvent mixture of acetone and water for

  obtain 1.5 g of 3- [2-aminoacetyl-5- (4- (3,4-dimethoxybenzoyl) -

  1-piperazinyl phenylpropionic acid.

F. 78.5-80.5 C.

REFERENCE EXAMPLE 11

  300 g (2.17 moles) of o-nitro-

  aniline in 620 ml of acetic anhydride and stirred at 40-50 ° C.

  for 3 hours. The reaction mixture is poured into ice water.

  The crystals which form are collected by filtration and dried. The o-acetylaminonitrobenzene thus obtained is suspended in 2.4 l of methanol. After addition of 20 g

  10% palladium on carbon, the suspension is subject to reduction

  catalytic reaction at ambient temperature and under pressure

  atmospheric. After the end of the reaction, the cata-

  filter and the solvent is distilled off under reduced pressure to precipitate the crystals which are then washed with ethanol and dried over phosphorus pentoxide

  under reduced pressure, to obtain 248 g of o-aminoacethani-

line.

REFERENCE EXAMPLE 12

  248 g (1.65 moles) of o-acetyl-

  aminoaniline in 1 liter of DMF and a solution of 114 g (0.87 mol) of chloride is added dropwise to the mixture with stirring.

  of 9-ethoxyacryl in 0.4 l of DMF, in 3 h 30 min at

  room temperature. The reaction mixture is then stirred at the same temperature for about 30 minutes: the reaction mixture is poured into ice water to precipitate the crystals which are

  collected by filtration to obtain 84.9 g of 1-acetylamino-2-

(9-éthoxyacryloylamido) benzene.

REFERENCE EXAMPLE 13

  84.9 g (0.34 mole) of 1-acetylamino-2- (ethoxyacryloylamido) benzene are added portionwise to the acid.

  sulfuric acid concentrated by stirring at room temperature.

  When the addition is complete, the mixture is stirred at room temperature.

  room temperature for 2 hours. The reaction mixture is poured

  in a large amount of ice water to precipitate the crystals which are collected by filtration to obtain 49.5 g of acetylaninocarbostyril.

REFERENCE EXAMPLE 14

  15.0 g (74.2 millimoles) of acetylaminocarbostyril are suspended in 300 ml of dioxane. After

  addition of 2.0 g of 10% palladium on carbon, the suspension is

  to catalytic reduction at 70-80 ° C under atmospheric pressure.

  pheric. When the reaction is complete, the cata-

  lyser by filtration and the solvent is distilled off

  reduced underpressure to obtain 14.3 g of 8-acetylamino-3,4-

dihydrocarbostyril.

REFERENCE EXAMPLE 15

  11.8 g (57.8 mmol) of 8-acetylamino-3,4-dihydrocarbostyril are suspended in 90 ml of 20% hydrochloric acid and the suspension is stirred with stirring under refluxing for 1 h. The reaction mixture is poured into ice water and neutralized with N sodium hydroxide and adjusted to about pH 8. Filtered by filtration

  precipitated crystals to obtain 7.87 g of 8-amino-3,4-di-

hydrocarbostyrile.

REFERENCE EXAMPLE 16

  21.5 g (0.106 mol) of 8-acetylaminocarbostyril are suspended in 190 ml of% hydrochloric acid and the suspension is stirred under reflux for 1 hour.

  The reaction mixture is poured into ice water and neutralized.

  read with 5N sodium hydroxide. The crystals are collected

  by filtration to obtain 15.47 g of 8-aminocarbostyril.

EXAMPLE 1

  After stirring for 15 hours, a mixture of 9.36 g of 6-amino-3,4-dihydrocarbostyril and 18 g of

  bis (β-bromoethyl) amine monobromide and 70 ml of methanol.

  After cooling, 3.06 g of sodium carbonate and

  the resulting mixture is refluxed for 8 hours with stirring.

  The reaction mixture is cooled to precipitate the crystals which are then collected by filtration, the crystals are washed.

  with methanol to obtain 9.1 g of 6- (1-piperyl)

  zinyl) -3,4-dihydrocarbostyril; F. 289-293 C (decomp.) (Methanol-

  water), in the form of colorless needles.

  Elemental analysis C (%) H (%) N (%) Calculated: 50.00 5.77 13.46 Found: 49, 95 5.82 13.50

EXAMPLE 2

  In a manner analogous to Example 1, 5- (1-piperazinyl) -3,4-dihydrocarbostyril monohydrochloride is obtained.

  monohydrate, F.> 300 C (methanol), in the form of colorless needles.

EXAMPLE 3

  A mixture of 9.36 g of 6-amino-3,4-dihydrocarbostyril, 18.3 g

  N, N-bis (3-bromoethyl) -3,4-dimethoxybenzamide and 70 ml of methanol.

  After cooling, 3.06 g of potassium carbonate are added and the mixture is refluxed for 8 hours with stirring. The reaction mixture is cooled to precipitate the crystals which are collected by filtration. Recrystallization in the mixture

  ethanol-chloroform gives 8.5 g of 6- [4- (3,4-dimethoxybenzoyl) -1-

  piperazinyl] -3,4-dihydrocarbostyril; Mp 238-239.5 ° C, colorless granules. Elemental Analysis C (7) H (%) N (%) Calculated: 66.84 6.33 10.63 Found: 66, 71 6.51 10.52

EXAMPLES 4-91

  In a similar manner to Example 3, the

  following compounds using the appropriate starting materials.

EXAMPLE 4

  6-44- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  F. 196-198 ° C (ethanol), colorless needles.

EXAMPLE 5

  - [4- (p-toluenesulfonyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  F. 302-304 C (dimethylformamide), colorless powder.

EXAMPLE 6

  6- (4-Butyl-1-piperazinyl) -3,4-dihydrocarbostyril monohydrochloride

  hemihydrate, 279-281 ° C (decomp.) (methanol).

EXAMPLE 7

  - (4-Benzoyl-1-piperazinyl) -3,4-dihydrocarbostyril, m.p. 248-251 ° C

(ethanol), colorless needles.

EXAMPLE 8

  6- (4-Benzoyl-1-piperazinyl) -3,4-dihydrocarbostyril, m.p. 221-222.5 ° C

(ethanol), pale yellow granules.

EXAMPLE 9

  - [4- (3,4-dimethoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  207-208 ° C (ethanol), colorless powder.

EXAMPLE 10

  - [4- (3,4,5-trimethoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  250-251.5 ° C (isopropanol), colorless granules.

EXAMPLE 11

  6- [4- (3,4,5-trimethoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  180-182 ° C (isopropanol), colorless granules.

EXAMPLE 12

  6- [4- (4-methoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril

  hemihydrate, 212-213 ° C (methanol), colorless needles.

EXAMPLE 13

  6- (4-acetyl-1-piperazinyl) -3,4-dihydrocarbostyril, mp 203-205 ° C

  (isopropanol), pale yellowish brown needles.

EXAMPLE 14

  6- (4-furoyl-1-pipdrazinyl) -3,4-dihydrocarbostyril, m.p. 206.5-207.5 ° C.

(ethanol), pale yellow granules.

EXAMPLE 15

  6- [4- (2-propynyl) -l-piperazinyl] -3,4-dihydrocarbostyril; 174-176 ° C (isopropanol).

EXAMPLE 16

  6-'4- (4-chlorobenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  M.p. 233-235 C, yellow needles (methanol).

EXAMPLE 17

  - [4- (3,4-dichlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  250-252 ° C (methanol), colorless powder.

EXAMPLE 18

  5- [4- (3,5-dichlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  255-257 ° C (methanol-chloroform), colorless needles.

EXAMPLE 19

  6- [4- (4-bromobenzoyl) 1 - piperazinyl] -3,4-dihydrocarbostyril,

  Mp 233-234.5 ° C, colorless granules (methanol-chloroform).

EXAMPLE 20

  [4- (4-cyanobenzoyl) -1H-piperazinyl] -3,4-dihydrocarbostyril

  Mp 266-269 C, colorless granules (methanol-chloroform).

EXAMPLE 21

  6- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

* 235.5-236.5 ° C (methanol-chloroform), yellow flakes.

EXAMPLE 22

  6- [4- (3,5-dinitrobenzoyl) -l1-piperazinyl] -3,4-dihydrocarbostyril,

  Mp 262-264 ° C (methanol-chloroform), reddish black needles.

EXAMPLE 23

  6- [4- (4-aminobenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  Mp 244-246 C, pale yellow needles (ethanol).

EXAMPLE 24

  - [4- (4-hydroxybenzoyl) -1-pipérazinyll] -3,4-dihydrocarbostyril,

  F.> 300 C (methanol-chloroform), colorless granules.

EXAMPLE 25

  6- [4- (3,4-methylenedioxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbo-

  styrile, 191-192.5 ° C (methanol), colorless needles.

EXAMPLE 26

  - [4- (4-methylbenzoyl) 1 - piperazinyl] -3,4-dihydrocarbostyril,

  Mp 239.5-240 ° C (chloroform-ether), colorless powder.

EXAMPLE 27

  6- [4- (methanesulfonyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  Mp 241.5-243 ° C, colorless granules (methanol).

EXAMPLE 28

  5- (4-ethyl-1-piperazinyl) -3,4-dihydrocarbohydrochloride

  styrile, F. 293-296 C (decomp.) (ethanol), colorless granules.

EXAMPLE 29

  6- (4-allyl-1-piperazinyl) -3,4-dihydrocarbostyril, m.p. 175-176 ° C .;

  (chloroform-ether), colorless flakes.

EXAMPLE 30

  5- [4- (2-propynyl) -1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 225-226 ° C.

(chloroform), pale yellow powder.

EXAMPLE 31

  6- [4- (2-buten-nyl) -1-piperazinyl] -3-dihydrocarbostyril, m.p. 242-245 ° C (decomp.).

EXAMPLE 32

  l-benzyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbo-

  styryl hemihydrate, m.p. 131.5-132.5 ° C (ethanol), yellow powder.

EXAMPLE 33

  l-allyl-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl) -1-piperazinyl] -

  3,4-dihydrocarbostyril hemihydrate, m.p. 120-122 ° C (methanol-ether),

colorless granules.

EXAMPLE 34

  (2-Propynyl) -6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril, mp 152-154 ° C (ethanol), pale yellow needles.

EXAMPLE 35

  1-methyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperylyl] -3,4-dihydro-

  carbostyril, 146.5-147.5 ° C (isopropanol), pale yellow granules.

EXAMPLE 36

  8-methoxy-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril, m.p. 162.5-163.5 ° C (isopropanol), colorless needles.

EXAMPLE 37

  6- [4- (3-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  Mp 195-197.5 ° C, colorless flakes (methanol).

EXAMPLE 38

  5- [4- (4-methoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  219-220 C (methanol-chloroform), colorless needles.

EXAMPLE 39

  - (4-ethoxycarbonylmethyl-1-piperazinyl) -3,4-dihydrocarbostyril,

  F. 206-208 C (methanol), colorless needles.

EXAMPLE 40

  [4- (4-Formyl-1-piperazinyl) -3,4-dihydrocarbostyril, mp 263-265 ° C,

colorless granules (methanol).

EXAMPLE 41

  6- (4-ethoxycarbonyl-l-piperazinyl) -3,4-dihydrocarbostyril,

  F. 182.5-184 C, colorless needles (isopropanol).

EXAMPLE 42

  5- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  194-196C (methanol), colorless needles.

EXAMPLE 43

  6- [4- (2-phenethyl) -1-piperazinyl] -3,4-dihydrohydrochloride monohydrochloride

  carbostyril, 274-276 ° C (decomp.) (methanol), colorless powder.

EXAMPLE 44

  6- [4- (4-chlorobenzyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  190-191.5 ° C (chloroform-methanol), colorless needles.

EXAMPLE 45

  5- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -3,4-monhydrochloride

  dihydrocarbostyril monohydrate, m.p. 298.5-300 ° C (decomp.)

(methanol), colorless granules.

EXAMPLE 46

  - [4- (4-nitrobenzyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  F. 268-271 C (decomp.) (Methanol), pale yellow powder.

EXAMPLE 47

  5- [4- (4-Aminobenzyl) -1-piperazinyl] -3,4-dihydrohydrochloride dihydrochloride

  carbostyril monohydrate, mp 224-227 ° C (decomp.) (methanol-ether),

yellow granules.

EXAMPLE 48

  6- [4- (4-methylbenzyl) -1-piperazinyl] -3,4-dihydro-dihydrochloride

  carbostyril, 272-273 ° C (decomp.) (methanol-water), colorless powder.

EXAMPLE 49

  5- [4- (3,4-Dimethoxybenzyl) -1-piperazinyl] -3,4-dihydrochloride

  dihydrocarbostyril, mp 270-272.5 ° C (decomp.).

EXAMPLE 50

  6- (4-ethoxycarbonyl-1-piperazinyl) carbostyril, m.p. 223-224 ° C

(m4thanol), yellow needles.

EXAMPLE 51

  6- [4- (3-chlorobenzoyl) -1-piperazinyl] carbostyril, m.p. 250.5-252 ° C

  (methanol-chioroform), yellow powder.

EXAMPLE 52

  6- [4- (4-Chlorobenzoyl) -1-piperazinyl] carbostyril, mp 265-266 ° C

  (methanol-chloroform), yellow powder.

EXAMPLE 53

  6- [4- (4-methoxybenzoyl) -1-piperazinyl] carbostyril, m.p. 230-233 ° C.

  (methanol-chloroform), yellow needles.

EXAMPLE 54

  6- [4- (3,4-dimethoxybenzoyl) -l-piperazinyl] carbostyril

  265-266.5 ° C (decomp.) (Methanol-chloroform), yellow granules.

EXAMPLE 55

  6- [4- (3,4,5-trimethoxybenzoyl) -l-piperazinyl] -carbostyrile,

  249.5-250 ° C (methanol-chloroform), yellow needles.

EXAMPLE 56

  6- [4- (4-cyanobenzoyl) -1-piperazinyl] carbostyril, m.p. 300-301 ° C

  (decomp.) (ethanol-chloroform), yellow powder.

EXAMPLE 57

  6- [4- (3,4-methylenedioxybenzoyl) -l-piperazinyl] -carbostyrile,

  266-267 ° C (decomp.) (Methanol-chloroform), yellow powder.

EXAMPLE 58

  6- [4- (4-Nitrobenzoyl) -1-piperazinyl] carbostyril, mp 265-266 ° C

  (decomp.) (methanol-chloroform), yellow needles.

EXAMPLE 59

  6- [4- (4-Aminobenzoyl) -1-piperazinyl] carbostyril, mp 287-290 ° C

  (chloroform-methanol), yellow powder.

EXAMPLE 60

  6- (4-b.enzoyl-1-piperazinyl) carbostyril, mp 264-265 ° C (ethanol-

chloroform), yellow needles.

EXAMPLE 61

  - [4- (4-acdtylaminobenzoyl) 1 - pipdrazinyl] -3,4-dihydrocarbostyril

  Mp 300 ° C (chloroform-ethanol), colorless powder.

EXAMPLE 62

  6- [4- (4-formyl) -1-piperazinyl] carbostyril, m.p. 286.5-288 ° C (methacrylate);

nol), yellow glitter.

EXAMPLE 63

  6- [4- (4-methylthiobenzoyl) -1-piperazinyl] carbostyril, m.p. 247.5-249, C

  (chloroform-methanol), yellow needles.

EXAMPLE 64

  6- [4- (3-pyridylcarbonyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  250-252 ° C (ethanol), yellow needles.

EXAMPLE 65

  6- [4- (4-méthoxyphénylacétyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  266-268.5 ° C (methanol), yellow powder.

EXAMPLE 66

  6- (4-phenylpropionyl-1-piperazinyl) -3,4-dihydrocarbostyril,

  F. 189.5-191 ° C (chloroform-methanol), yellow granules.

EXAMPLE 67

  8- (4-benzoyl-1-piperazinyl) carbostyril, mp 244-245 ° C (ethanol),

colorless powder.

EXAMPLE 68

  8- [4- (4-chlorobenzoyl) -1-piperazinyl] carbostyril, m.p. 255.5-257 ° C

  (ethanol-chloroform), colorless powder.

EXAMPLE 69

  8- [4- (3-chlorobenzoyl) -1-piperazinyl] carbostyril, mp 208-209 ° C

(ethanol), colorless granules.

EXAMPLE 70

  8- [4- (2-chlorobenzoyl) -1-piperazinyl] carbostyril, m.p. 239-240.5 ° C

(Ethanol), colorless needles.

EXAMPLE 71

  8- [4- (4-methoxybenzoyl) -1-piperazinyl] carbostyril, mp 208-210 ° C

(ethanol), colorless flakes.

EXAMPLE 72

  8- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] carbostyril, mp 197-198 ° C

  (ethanol-ether), colorless flakes.

EXAMPLE 73

  8- [4- (3,4-methylenedioxybenzoyl) -l1-piperazinyl] -3,4-dihydrocarbo-

  styrile, m.p. 195-L97 C (ethanol), colorless flakes.

EXAMPLE 74

  8- [4- (3-chlorobenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  F. 152-154 ° C (ethanol) colorless flakes.

EXAMPLE 75

  8- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril

  Mp 145-148 ° C, colorless flakes (ethanol).

EXAMPLE 76

  8- [4- (4-methylthiobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril

  178-179.5 ° C (colorless granules (ethanol).

EXAMPLE 77

  7- [4- (2-chlorobenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  194-195.5 ° C (methanol), colorless needles.

EXAMPLE 78

  7- [4- (3-chlorobenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

  F. 136.5-138.5 ° C (ethanol), colorless powder.

EXAMPLE 79

  7- [4- (4-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  Mp 289-291 ° C, colorless powder (chloroform-methanol).

EXAMPLE 80

  7- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril

  M.p. 231-233 C, colorless needles (ethanol).

EXAMPLE 81

  7- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbo-

  styrile, 207-208 ° C (ethanol), colorless powder.

EXAMPLE 82

  7- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  240-242 ° C (chloroform-methanol), yellow granules.

EXAMPLE 83

  7- [4- (3,4,5-trimethoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbo-

  styrile, F. 195-196.5 ° C (methanol), colorless rhombic crystals.

EXAMPLE 84

  7- (4-benzoyl-1-piperazinyl) -3,4-dihydrocarbostyril, m.p. 264.5-265.5 ° C

  (chloroform-m ethanol), colorless needles.

EXAMPLE 85

  7- [4- (3,4-Dimethoxybenzoyl) -1H-piperazinyl] -3,4-dihydrocarbostyril, m.p. 118-120 ° C (ethanol, dried under reduced pressure at 80 ° C, for h), colorless granules.

EXAMPLE 86

  7- [4- (4-methylthiobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  258-2600C (chloroform-methanol), colorless rhombic crystals.

EXAMPLE 87

  7- (4-phenylpropionyl-1-piperazinyl) -3,4-dihydrocarbostyril,

  183-184C, colorless needles (ethanol).

EXAMPLE 88

  6- [4- (4-methoxyphenylacetyl) -1-piperazinyl] carbostyril, m.p. 224-225 ° C

(ethanol), yellow needles.

EXAMPLE 89

  6- [4- (4-hydroxyphenylacetyl) -1-piperazinyl] carbostyril, m.p.

(DMF), yellow powder.

EXAMPLE 90

  - [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  F. 292-294 C (decomp.) (Methanol-chloroform), yellow granules.

EXAMPLE 91

  5- [4- (4-aminobenzoyl) -1-pipérazinyll] -3,4-dihydrocarbostyril,

  F. 285-287 C (decomp.) (Ethanol-chloroform), colorless granules.

EXAMPLE 92

  3.5 g of monobromide of

  6- (1-piperazinyl) -3,4-dihydrocarbostyril in 40 ml of dimethyl

  formamide (hereinafter abbreviated as DMF). After addition of 960 mg of sodium bicarbonate, the suspension is stirred at room temperature for 30 minutes to convert the starting compound to 6 (1-piperazinyl) 3,4-dihydrocarbostyril. 2.36 ml of triethylamine are then added to the mixture and the mixture is stirred at ambient temperature by slowly adding dropwise 10 ml of solution.

  containing 2.9 g of 3,4-dimethoxybenzoyl chloride in DMF.

  When the addition is complete, the reaction mixture is stirred for 30 minutes. The mixture is poured in a large quantity

  saturated solution of sodium chloride and extracted with

  form. The extract is washed with saturated sodium bicarbonate solution and then with water and dried over sodium sulfate.

  Anhydrous. The chloroform is distilled off and recreated

  tallizes the residual crystals in the chloroform-ethanol mixture

  to obtain 3.8 g of 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3.4-

  dihydrocarbostyril, mp 238-239.5 ° C, colorless granules.

  Elemental analysis C (%) H (%) N (%) Calculated: 66.84 6.33 10.63 Found: 66, 69 6.49 10.51 In a similar manner to Example 92, the same compounds are prepared than those obtained in Examples 7-14, 32-36, 41, 50-61

  and 63-91 using the appropriate starting materials.

EXAMPLE 93

  1 g of monobromide of

  6- (1-piperazinyl) -3,4-dihydrocarbostyril in 15 ml of DMF.

  After addition of 296 mg of sodium bicarbonate, the suspension is stirred

  pension at room temperature for 30 min to transform

  the starting compound of 6- (1-piperazinyl) -3,4-dihydrocarbostyril.

  0.62 ml of triethylamine are then added to the mixture and the mixture is stirred at room temperature by slowly adding dropwise ml of solution containing 532 mg of m-chlorobenzoyl chloride in DMF. After the addition is complete, the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with saturated sodium bicarbonate solution and then with water and dried over anhydrous sodium sulfate. The chloroform is distilled off and the residual crystals are recrystallized from methanol to give

  0.4 g of 6- (4- (3-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbon

  styrile, F. 197-197.5 ° C, colorless flakes.

  Analysis element C (%) H (M) N (%) Calculated: 65.04 5.42 11.38 Found: 64.99 5, 35 11.45

EXAMPLE 94

  3.5 g of monobromide of

  6- (1-piperazinyl) -3,4-dihydrocarbostyril in 40 ml of DMF.

  After adding 960 mg of sodium bicarbonate, the suspension is stirred at room temperature for 30 minutes to transform

  the starting compound of 6- (1-piperazinyl) -3,4-dihydrocarbostyril. 2.36 ml of triethylamine are then added to the mixture and the mixture is stirred for

  mixture at room temperature by slowly adding dropwise ml of solution containing 2.5 g of 4-chlorobenzoyl chloride in DMF. When the addition is complete, the reaction mixture is stirred for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with a saturated solution of sodium bicarbonate

  and then with water and dried over anhydrous sodium sulfate.

  Chloroform is distilled off and recrystallized

  residual crystals in methanol to obtain 0.7 g of 6- [4- (4-

  chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 233-235 ° C,

* pale yellow needles.

  Elemental analysis C (2) H (%) N (%) Calculated: 65.04 5.42 11.38 Found: 64, 89 5.30 11.51

EXAMPLE 95

  2.6 g of 5- (1-piperobuty) monobromide are dissolved

  zinyl) -3,4-dihydrocarbostyril and 2.34 ml of triethylamine in 1 ml of DMF. The mixture is stirred at ambient temperature by slowly adding dropwise 10 ml of a solution containing

  2.5 g of 4-methoxybenzoyl chloride in DMF. When the addi-

  After completion, the reaction mixture is stirred for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with a saturated solution of sodium bicarbonate and then with water and dried

  on anhydrous sodium sulphate. The chloroform is distilled off

  and recrystallize the residual crystals in the mixture

  methanol-chloroform to give 1.1 g of 5- [4- (4-methoxybenzoyl) -

  1-piperazinyl] -3,4-dihydrocarbostyril, mp 219-220 ° C, colorless needles. Elemental analysis C (%) H (%) N (%) Calculated: 69.04 6.30 13.15 Found: 68, 95 6.21 13.25

EXAMPLE 96

  3.5 g of - (i-piperazinyl) -3,4-dihydrocarbostyril monobromide in 40 ml of DMF are suspended. After adding 960 mg of sodium bicarbonate, the suspension is stirred at room temperature for 30 minutes to convert the starting compound to 5- (1-piperazinyl) -3,4-dihydrocarbostyril.

  2.34 ml of triethylamine are then added and the mixture is stirred at room temperature.

  by slowly adding dropwise 10 ml of a solution containing 3.0 g of 3,5-dichlorobenzoyl chloride in DMF. When the addition is complete, the reaction mixture is stirred for 40 minutes. The reaction mixture is poured into a large amount of saturated sodium chloride solution and extracted with chloroform. The extract is washed with a saturated solution of sodium bicarbonate and then with water and dried

  on anhydrous sodium sulphate. The chloroform is distilled off

  and recrystallize the residual crystals in the mixture

  methanol-chloroform to give 1.8 g of 5- [4- (3,5-dichloro-

  benzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 255-257 ° C,

colorless needles.

  Elemental analysis C (% 7) H (M) N (%) Calculated: 59.55 4.71 10.42 Found: 59, 43 4.83 10.31

EXAMPLE 97

  2.6 g of 6- (1-piperazinyl) -3,4-dihydro-

  carbostyril and 1 g of sodium bicarbonate in 50 ml of dimethyl

  sulfoxide and the mixture is stirred under ice-cooling while slowly adding 20 ml of a solution

  dimethylsulfoxide containing 3.2 g of 4-bromobenzoylchloride.

  When the addition is complete, the reaction mixture is stirred at room temperature for 60 minutes. Pour the mixture of

  reaction in a large quantity of water and extracted with

  form. The extract is washed with saturated sodium bicarbonate solution and then with water and dried over sodium sulfate.

  Anhydrous. The chloroform is distilled off and recrystallized.

  read the residual crystals in the methanol-chloroform mixture

  to obtain 0.8 g of 6- [4- (4-bromolbenzoyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril, mp 233-234.5 ° C, colorless granules.

  Elemental analysis C (%) H (%) N (%) Calculated: 57.97 4.83 10.14 Found: 57, 79 4.71 10.23

EXAMPLE 98

  2.6 g of 5- (1-piperazinyl) -3,4-dihydro-

  carbostyril and 2 ml of trimethylamine in 40 ml of DMF. The mixture is stirred at room temperature by slowly adding dropwise 10 ml of a DMF solution containing 2.4 g of 4cyanobenzoyl chloride. When the addition is complete, the reaction mixture is stirred at 40-50 ° C for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with sodium bicarbonate solution and then with water and dried over sodium sulfate.

  Anhydrous. The chloroform is distilled off and recrystallized.

  read the residual crystals in the methanol-chloroform mixture

  to obtain 1.9 g of 5- [4- (4-cyanobenzoyl) -1-piperazinyl] -3.4-

  dihydrocarbostyrile, mp 266-269 C, colorless granules.

  Elemental analysis C (%) H (%) N (%) Calculated: 70.00 5.56 15.56 Found: 70, 14 5.71 15.43

EXAMPLE 99

  2.6 g of 6- (1-piperazinyl) -3,4-dihydro-

  carbostyril and 2 ml of pyridine to 40 ml of DMF. The mixture is stirred at room temperature by slowly adding dropwise 10 ml of a solution in DMF containing 2.7 g of 4-nitrobenzoyl chloride. When the addition is complete, the reaction mixture is stirred at the same temperature for 30 minutes. The reaction mixture is poured into a large amount of water and the chloroform is extracted. The extract is washed with sodium bicarbonate solution and then with water and dried over anhydrous sodium sulfate. The chloroform is distilled off and

  the residual crystals are recrystallized from the methanol

  chloroform to give 2.4 g of 6- [4- (4-nitrobenzoyl) -1-piperine

  razinyl] -3,4-dihydrocarbonstryl, m.p. 235-5-236.5C.

  Elemental analysis C (%) H (%) N (%) Calculated: 63.15 5.30 14.73 Found: 63, 09 5.35 14.77

EXAMPLE 100

  2.6 g of 6- (1-piperazinyl) -3,4-dihydro-

  carbostyril and 2.34 ml of triethylamine to 40 ml of dimethylsulfoxide

  and the mixture is stirred at room temperature by slowly adding

  dropwise 10 ml of a dimethylsulfoxide solution

  containing 3.3 g of 3,5-dinitrobenzoyl chloride. When the addi-

  After the reaction is complete, the reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with saturated sodium bicarbonate solution and then with water and dried over anhydrous sodium sulphate, the chloroform is distilled off and the residual crystals are recrystallized from the methanol-chloroform mixture to give

  give 0.3 g of 6- [4- (3,5-dinitrobenzoyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril; Mp 262-264 C, reddish black needles.

  Additional Analysis C (%) H (%) N (%) Calculated: 56.47 4.47 16.47 Found: 56.34 4.61 16.35

EXAMPLE 101

  400 mg of 6- [4- (4-nitrobenzoyl) -1-piperine

  razinyl] -3,4-dihydrocarbostyril in 20 ml of methanol and reduced to room temperature under atmospheric pressure using mg of 10% palladium on carbon as catalyst. After the end of

  the absorption of hydrogen, the catalyst is separated by filtration.

  The filtrate is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel. Recrystallization from ethanol gave 210 mg of 6- [4- (4-aminobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 244-246 ° C.

pale yellow needles.

  Elemental analysis C (%) H (%) N (M) Calculated: 68.57 6.29 16.00 Found: 68, 70 6.18 16.14 In a similar manner to Example 10, the following is prepared:

  5- [4- (4-Aminobenzyl) -1-piperazinyl] dihydrochloride monohydrate

  3,4-dihydrocarbostyril, mp 224-2270C (decomp.) (Methanol-ether),

yellow granules.

EXAMPLE 102

  A mixture of 300 mg of 5- [4- (4-

  methoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril and 7 ml of methylene chloride by slowly adding dropwise 2 ml of a solution in methylene chloride containing 226 mg of boron tribromide. When the addition is complete, the reaction mixture is stirred at the same temperature as above for 30 minutes and the temperature is raised to room temperature in about 1 hour. The reaction mixture is then poured into a large quantity

  of water and the crystals which precipitate are collected by filtration.

  Recrystallization of the crystals in the methanol-chloroform mixture

  gives 150 mg of 5- [4- (4-hydroxybenzoyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril, F.> 3000 C, colorless granules.

  Elemental analysis C (%) H (%) N (%) Calculated: 63.38 5.98 11.97 Found: 68, 21 6.11 11.83

EXAMPLE 103

  2.6 g of 5- (1-piperazinyl) -3,4-dihydrocar-

  bostyril and 4 ml of DBU at 40 ml of DMF. The mixture is stirred at ambient temperature by slowly adding dropwise 10 ml.

  of DMF solution containing 3.0 g of 3,4-dichloro-

  benzoyl. When the addition is complete, the reaction mixture is stirred for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with sodium bicarbonate solution and then with

  water and dried over anhydrous sodium sulfate. Chlorine

  roform by distillation and recrystallize the crystals

  in methanol to give 1.2 g of 5- [4- (3,4-dichlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 250-252 ° C,

colorless powder.

  Elemental analysis C (%) H (%) N (%) Calculated: 59.55 4.71 10.42 Found: 59, 38 4.82 10.34

EXAMPLE 104

  2.6 g of 6- (1-piperazinyl) -3,4-dihydro-

  carbostyril and 2.34 ml of triethylamine in 40 ml of DMF. The mixture is stirred at room temperature by slowly adding dropwise 10 ml of DMF solution containing 2.6 g of 3,4-methylenedioxybenzoyl chloride. When the addition is complete, the reaction mixture is stirred at room temperature for min. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with sodium bicarbonate solution and then with water and dried

  on anhydrous sodium sulphate. The chloroform is distilled off

  and recrystallize the residual crystals in the methacrylate.

  to obtain 1,6 g of 6- [4- (3,4-methylenedioxybenzoyl) -

  1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 191-192.5 C, needles

colorless.

  Elemental analysis C (%) H () N (%) Calculated: 66.49 5.54 11.08 Found: 66.35 5.67 10.94

EXAMPLE 105

  2.6 g of 5- (1-piperazinyl) -3,4-dihydro-

  carbostyril and 2.34 ml of triethylamine in 50 ml of chloroform.

  The mixture is stirred at room temperature by slowly adding dropwise 10 ml of chloroform solution containing 2: 3 g of 4-methylbenzoyl chloride. When the addition is complete, the reaction mixture is stirred for 30 minutes. After completion of the reaction, 100 ml of chloroform and then a large amount of water are added to separate the chloroform and the chloroform layer is washed with sodium bicarbonate solution and then with water and dried over sodium sulfate. anhydrous sodium. The chloroform is distilled off and the residual crystals are recrystallized from chloroform-ether to give 1.8 g of 3- [4- (4-methylbenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril.

Mp 239.5-240 ° C, colorless powder.

  Elemental analysis C (%) H (%) N (%) Calculated: 72.21 6.59 12.03 Found: 72, 34 6.44 11.94

EXAMPLE 106

  To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-

  dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of DMF, 720 mg of chloride-4-methoxybenzyl and onagitele melmge at 80 ° C for 2 h 30 min. The reaction mixture is poured into a large amount of saturated sodium chloride solution and extracted with chloroform. After washing with water, the extract is dried

  on anhydrous sodium sulphate. Chloform is distilled off

  and purify the residue by column chromatography on silica gel. Recrystallization from ethanol gives 950 mg of 6- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

F. 196-198 C, colorless needles.

  Elemental analysis C (%) H (%) N (7o) Calculated: 70.00 7.22 11.67 Found: 69, 91 7.15 11.71 In a similar manner to Example 106, the same compound is prepared than in Example 44 using appropriate starting materials.

EXAMPLE 107

  A mixture of 1.0 g of 5- (1-piperazinyl) -3,4-dihydrocarbosyril, 1.11 g of potassium carbonate, 760 mg of 4-methoxybenzyl chloride and stirred at 70.degree.-80.degree. 20 ml of DIF. The reaction mixture is poured into a large amount of water and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulphate. The chloroform is distilled off and the residue is purified by column chromatography on silica gel. Recrystallization in methanol

  gives 60 mg of 5- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril, m.p. 194-196C, colorless needles.

  Elemental analysis C (%) H (%) N (%) Calculated: 71.79 7.12 11.97 Found: 71, 84 7.05 11.89

EXAMPLE 108

  To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro-

  carbostyril ,. 1.17 g of potassium carbonate and 20 ml of DMF, 646 mg of 2-phenethyl chloride are added and the mixture is stirred at -100 ° C. for 2 h 30 min. The reaction mixture is poured into a large amount of water and extracted with chloroform. After

  washing with water, the extract is dried over anhydrous sodium sulphate.

  The chloroform is distilled off and the residue is purified.

  by silica gel column chromatography. After transformation

  In this case, the product is recrystallized from methanol to give 0.6 g of methanol in hydrochloric acid.

  6- [4- (2-phenethyl) -1-piperazinyl] -3,4-dihydro-hydrochloride

  carbostyril, 274-276 ° C (decomp.), colorless powder.

  Elemental analysis C (%) H (%) N (%) Calculated: 67.82 7.05 11.30 Found: 67, 85 6.93 11.39

EXAMPLE 109

  To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-

  dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of DMF, 858 mg of 3,4-dimethoxybenzyl chloride are added and the mixture is stirred at 70-80 ° C. for 2 hours. The reaction mixture is poured into a large amount of water and extracted with chloroform. After

  washing with water, the extract is dried over anhydrous sodium sulphate.

  The chloroform is distilled off and the residue is purified by column chromatography on silica gel. The residue is converted into hydrochloride to give 610 mg of [4- (3,4-dimethoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyril dihydrochloride,

F. 270-272.5 ° C (decomp.).

  Elemental analysis C (%) H (%) N (%) Calculated: 58.15 6.43 9.25 Found: 58, 08 6.51 9.14

EXAMPLE 110

  To a mixture of 1.0 g of 6- (1-piperazinyl) -3.4-

  dihydrocarbostyril, 1.11 g of potassium carbonate and 20 ml of DMF, 780 mg of 4-chlorobenzyl chloride are added and the mixture is stirred at 70 ° C. for 4 hours. Pour the reaction mixture

  in a large amount of water and extracted with chloroform.

  The chloroform is distilled off and the residue is purified.

  by silica gel column chromatography. The recrystalli-

  in the chloroform-methanol mixture gives 500 mg of 6- [4- (4-

  chlorobenzyl) -1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 190-191.51C.

colorless needles.

  Elemental analysis C (%) RH (%) N (%) Calculated: 67.51 6.23 11.81 Found: 67, 31 6.17 11.85

EXAMPLE 111

  To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-

  dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of DMF, 895 mg of 3,4-dichlorobenzyl chloride are added and the mixture is stirred at 60-70 ° C for 3 h. The reaction mixture is poured into a large amount of water and extracted with chloroform. After

  washing with water, the extract is dried over anhydrous sodium sulphate.

  The chloroform is distilled off and the residue is purified.

  by silica gel column chromatography. After transformation

  hydrochloride with methanolic hydrochloric acid,

  recrystallizes the product in methanol to obtain 0.17 g mono-

  5- [4- (3,4-dichlorobenzyl) -1-piperazinyl] hydrochloride monohydrate

  3,4-dihydrocarbostyril, mp 298.5-300 ° C (decomp.), Colorless granules.

  Elemental analysis C (%) H (o) N (%) Calculated: 54.00 5.44 9.45 Found: 53.73 5.57 9.29

EXAMPLE 112

  To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-

  dihydrocarbostyril, 1.17 g of potassium carbonate and 50 ml of benzene, 789 mg of 4-nitrobenzyl chloride are added and the mixture is stirred under reflux for 4 hours. When the reaction is complete, the benzene is distilled off and the residue is dissolved in chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulphate. The chloroform is distilled off and the residue is purified by chromatography on

  column of silica gel. Recrystallization in the chlorinated

  form-ether gives 0.26 g of 5- [4- (4-nitrobenzyl) -1-piperazinyl] -3.4-

  dihydrocarbostyrile, mp 268-271 C (decomp.), pale yellow powder.

  Elemental analysis C (%) H (%) N (%) Calculated: 65.57 6.01 15.30 Found: 65343 5.89 15.42

EXAMPLE 113

  To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-di-

  hydrocarbon, 1.17 g of potassium carbonate and 20 ml of dimethylsulfoxide, 650 mg of 4-aminobenzyl chloride

  and stirred at 80 ° C. for 2 h 30 min. The reaction mixture is poured

  in a large amount of water and extracted with chloroform.

  After washing with water, the extract is dried over anhydrous sodium sulphate. The chloroform is distilled off and the residue is purified by column chromatography on silica gel. After

  hydrochloride conversion by methanol-chloroacid

  water, the product is recrystallized from methanol-ether

  to obtain 0.4 g of 5- [4- (4-amino) dihydrochloride monohydrate

  benzyl) -1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 224-227 ° C (decomp.),

yellow granules.

  Elemental analysis C (%) H (%) N (%) Calculated: 56.20 6.60 13.11 Found: 56, 19 6.57 13.31

EXAMPLE 114

  To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-

  dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of

  methylphosphorotriamide, 651 mg of 4-hydroxychloride

  benzyl and the mixture is stirred at 90 ° C. for 2 h 30 min. The reaction mixture is poured into a large amount of water and extracted with chloroform. After washing with water, the extract is dried

  anhydrous sodium sulphate. The chloroform is distilled off

  and purify the residue by column chromatography.

  silica gel to obtain 0.3 g of 6- [4- (4-hydroxybenzyl) -1-

  piperazinyl] -3,4-dihydrocarbostyril.

  Elemental analysis C (%) H (%) N (%) Calculated: 14.24 6.82 12.46 Found: 14, 33 6.74 12.37

EXAMPLE 115

  To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro-carbostyrene, 1,17 g of potassium bicarbonate and 20 ml of DMF, 646 mg of 4-methylbenzyl chloride and the mixture is stirred at 80 ° C. for 2 h 30 min. The reaction mixture is poured into a large amount of water and extracted with chloroform. After

  washing with water, the extract is dried over anhydrous sodium sulphate.

  The chloroform is distilled off and the residue is purified by chromatography on a column of silica gel. After conversion to the hydrochloride by methanol-hydrochloric acid mixture, the product is recrystallized from methanol to form

  0.17 g of 6- [4- (4-methylbenzyl) -1-piperazinyl dihydrochloride]

  3,4-dihydrocarbostyril, 272-273 ° C (decomp.), Colorless powder.

  Elemental analysis C () H (%) N (%) Calculated: 61, 191 6,63 10.32 Found: 61, 86 6.59 10.39

EXAMPLE 116

  To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-

  dihydrocarbostyril, 1.17 g of potassium carbonate and 50 ml of benzene, 688 mg of 4-cyanobenzylethane chloride are added and the mixture is refluxed for 3 hours. The reaction mixture is poured into a large amount of saturated sodium chloride solution and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulphate. The chloroform is distilled off and the residue is purified by chromatography on

  column of silica gel to obtain 105 mg of 5- [4- (4-cyanobenzyl) -

  1-piperazinyl) -3,4-dihydfocarbostyrile.

  Elemental analysis C (%) H (%) N (%) Calculated 72.83 6.36 16.18 Found: 72.92 6.51 16.07

EXAMPLE 117

  To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro-

  carbostyril, 1.17 g of potassium carbonate and 20 ml of DMF, 785 mg of 3,4-methylenedioxybenzyl chloride are added and the mixture is stirred at 80-90 ° C. for 3 h 30 min. The reaction mixture is poured into a large amount of saturated sodium chloride solution and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulphate. The chloroform is distilled off and the residue is purified by silica gel column chromatography to obtain 0.2 g of

  6- [4- (3,4-methylenedioxybenzyl-1-piperazinyl) -3,4-dihydrocarbyl)

  styrile. Elemental analysis C (%) H (%) N (%) Calculated: 69.04 6.30 11.51 Found: 68.89 6.43 11.42

EXAMPLE 118

  1.0 g of 5- (1-piperazinyl) -3,4-dihydro-

  carbostyril to a mixture of 10 ml of DMF and 0.85 ml of trimethyl

  The mixture is stirred at room temperature by slowly adding dropwise 5 ml of DMF solution containing 1.07 g of p-toluenesulfonyl chloride. When the addition is complete, the reaction mixture is stirred at the same temperature as above for 30 minutes. The reaction mixture is poured into a large amount of saturated sodium chloride solution and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The chloroform is distilled off and the residual crystals are recrystallized from

  DMF to obtain 800 mg of 5- [4- (p-toluenesulfonyl) -1-piperazinyl] -

  3,4-dihydrocarbostyril, mp 302-304 ° C, colorless powder.

  Elemental analysis C (70) H (%) N (70) Calculated: 62.34 5.97 10.91 Found: 62, 43 5.89 10.79

EXAMPLE 119

  1.0 g of 6- (1-piperazinyl) -3,4-dihydrocar-

  bostyrile to a mixture of 10 ml of DMF and 0.85 ml of trimethylamine and the mixture is stirred at room temperature by slowly adding dropwise 5 ml of DMF solution containing 440 mg of methanesulfonyl chloride. When the addition is complete, the reaction mixture is stirred at the same temperature as above for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The chloroform is distilled off and the crystals are recrystallized

  residuals in methanol to obtain 0.17 g of 6- (4-mgthane-

  sulfonyl-1-piperazinyl) -3,4-dihydrocarbcstyril, m.p. 241.5-243 ° C, colorless granules. Elemental analysis C (%) H () N (%) Calculated: 54.37 6.15 13.59 Found: 54.23 6.24 13.43

EXAMPLE 120

  To a mixture of 1 g of 6- (1-piperazinyl) -3,4-dihydro-

  carbostyril, 30 ml of DMF and 900 mg of potassium carbonate, 2 ml of butyl bromide are added and the mixture is stirred at 80 ° C. for 2 h 30 min. The reaction mixture is poured into a large amount of saturated sodium chloride solution and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulphate. The chloroform is then distilled off and the residue is purified by column chromatography on silica gel. After conversion into the hydrochloride salt by methanol-hydrochloric acid, the product is recrystallized from methanol to give 700 mg of 6- (4-butyl-lopiperazinyl) -3,4-dihydrocarbospyril hydrochloride hemihydrate, mp 279-281 ° C. ( decomp.). Elemental analysis C (%) H (%) N (%) Calculated: 61.46 7.53 12.65 Found: 61.34 7.45 12.51 In a similar manner to Example 120, the same than those obtained in Examples 15 and 39 in

  using appropriate starting materials.

EXAMPLE 121

  To a mixture of 1 g of 5- (1-piperazinyl) -3,4-dihydro-

  carbostyril, 20 ml of DMSO and 1.7 g of potassium carbonate, 450 mg of ethyl bromide are added and the mixture is stirred at 70-100 ° C. for 4 h 30 min. The reaction mixture is poured into a large amount of water and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulphate. The chloroform is then distilled off and the residue is purified by column chromatography on silica gel. After conversion into hydrochloride by the methanol hydrochloric acid mixture, the product is recrystallized from methanol to obtain 0.14 g of

  5- (4-ethyl-1-pSpezizinyl) -3,4-dihydrocarbohydrochloride

  styrile, F. 293-296 C (decomp.), colorless granules. Elemental analysis C (%) H (%) N (%) Calculated: 61.01 7.46 14.24 Found: 61.08 7.41 14.19

EXAMPLE 122

  To a mixture of 1 g of 6- (1-piperazinyl) -3,4-dihydro-

  carbostyril, 15 ml of DMF and 1.82 g of potassium carbonate,

  500 mg of allyl bromide are added and the mixture is stirred at room temperature.

  room temperature for 2 hours. The reaction mixture is poured into a large amount of water and extracted with chloroform. After

  washing with water, the extract is dried over anhydrous sodium sulphate.

  The chloroform is then distilled off and the residue is purified by column chromatography on silica gel and recrystallized from chloroform-ether to give 0.43 g of 6 (4-allyl-1-piperazinyl) -3. 4-dihydrocarbostyril,

175-176 ° C, colorless flakes.

  Elemental analysis C (%) H (7%) N (%) Calculated: 70.84 7.75 15.50 Found: 70, 73 7.81 15.38

EXAMPLE 123

  To a mixture of 1 g of 5- (1-piperazinyl) -3,4-dihydro-

  carbostyril, 30 ml of DMF and 900 mg of sodium carbonate, 491 mg of propargyl bromide are added and the mixture is stirred at C for 3 h. The reaction mixture is poured into a large amount of saturated sodium chloride solution and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulphate. The chloroform is then distilled off and the residue is purified by column chromatography.

  silica gel and recrystallized from chloroform to obtain

  Add 0.1 g of 5- [4- (2-propynyl) -1-piperazinyl] -3,4-dihydrocarbon

  styrile, 225-226 ° C, pale yellow powder.

  Elemental analysis C (%) H (%) N (%) Calculated: 71.38 7.06 15.61 Found: 71, 23 7.14 15.48

EXAMPLE 124 To a mixture of 1 g of 6- (1-piperazinyl) -3,4-dihydro-carbostyril, 30 ml

  of DMF and 900 mg of sodium bicarbonate, 600 mg of 3-methylallyl bromide are added and the mixture is stirred at C for 2 h 30 min. The reaction mixture is poured into a large amount of saturated sodium chloride solution and extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulphate. The chloroform is then distilled off and the residue is purified by column chromatography on silica gel. After conversion into hydrochloride by the methanol-hydrochloric acid mixture, the product is recrystallized.

  in methanol to give 0.4 g of 6- [4- (2-

  butenyl) -1-piperazinyl] -3,4-dihydrocarbostyril, m.p. 242-245 ° C.

(decomp.), colorless flakes.

  Elemental analysis C (7.) H (%) NI () Calculated: 56.98 7.03 11.73 Found: 56, 92 6.72 11.77

EXAMPLE 125

  500 mg of 6- [4- (3,4-dimethoxybenzoyl) -l-

  piperazinyl] -3,4-dihydrocarbostyril and 70 mg of 607 oily sodium hydride with 5 ml of DMF and stirred at room temperature for 1 hour. 3 ml of DMF solution containing 0.17 ml of benzyl chloride is then added dropwise. After stirring the mixture at room temperature for 4 hours, the reaction mixture is poured into a large amount of water and the organics are extracted with chloroform. The chloroform layer is washed with water and dried. The chloroform is distilled off and the residue is recrystallized from ethanol to give

* obtain 150 mg of 1-benzyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -

  3,4-dihydrocarbostyrilheihydrate, mp 131.5-132.5 ° C, yellow powder.

  Elemental analysis C (%) H (%) N (%) Calculated: 70.43 6.52 8.50 Found: 70.60 6.45 8.46 In a similar manner to Example 125, the same compound is prepared than that obtained in Example 35 using products

appropriate starting points.

EXAMPLE 126

  1.96 g of 5- [4- (3,4-dimethoxybenzoyl) -1-

  piperazinyl] -3,4-dihydrocarbostyril and 0.20 g of sodium amide with 60 ml of DMP and stirred at room temperature for 2 h. 0.67 g of allyl chloride is then added to the mixture and the mixture is stirred at room temperature for 10 hours. The reaction mixture is poured into 150 ml of saturated chloride solution

  of sodium and the organic substances are extracted with chloroform.

  The chloroform layer is washed with water and dried. The chloroform is distilled off and the residue is purified by column chromatography on silica gel and then recrystallized.

  in the methanol-ether mixture to obtain 1.76 g of 1-allyl-5- [4-

  (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril

  hemihydrate, m.p. 120-122 ° C, colorless granules.

  Elemental analysis C (%) H (%) N (%) Calculated: 67.57 6.53 9.46 Found: 67.49 6.59 9.38

EXAMPLE 127

  1.66 g of 6- [4- (3,4-dimethoxybenzoyl) -1-

  piperazinyl] -3,4-dihydrocarbostyril and 0.25 g of 507 oily sodium hydride with 60 ml of DMF and stirred at room temperature for 2 h. 0.66 g of propargyl chloride are then added to the mixture and the mixture is stirred at ambient temperature for 7 hours. The reaction mixture is poured into 150 ml of saturated sodium chloride solution and the organic substances are extracted with chloroform. The chloroform layer is washed with water and dried. The chloroform is distilled off and the residue is purified by column chromatography on silica gel, followed by

  recrystallized from ethanol to give 0.34 g of 1- (2-propynyl) -

  6- [4- (3,4-dimethoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

Mp 152-154 C, pale yellow needles.

  Elemental analysis C (%) H (%) N (%) Calculated: 69.27 6.28 9.69 Found: 69.36 6.39 9.57

EXAMPLE 128

  To a solution of 9.36 g of 6-amino-3,4-dihydrocar-

  bostyril in 70 ml of methanol, 13.5 g of bis-O-bromine are added.

  ethyl ether and stirred at reflux for 10 h. After cooling, 3.06 g of potassium carbonate are added to the reaction mixture and the mixture is stirred under reflux for 10 hours. After cooling, the crystals formed are collected by filtration. The crystals thus obtained are dissolved in 40 ml of water and the solution is weakly alkalinized with a dilute aqueous solution of sodium hydroxide. Hunting

  the mother liquor by distillation and add to the residue of the iso-

  propanol to precipitate crystals which are then collected by

  filtration to obtain 4.7 g of 6- (4-morpholino; -3,4-dihydrocarbo-

  styrile. The production of this compound is confirmed by the spectra

IR and NMR.

  Elemental analysis C (%) H (%) N (7) Calculated: 67.24 6.90 12.07 Found: 67, 12 7.02 11.98 (b) A mixture of 2, 32 g

  6-morpholino-3,4-dihydrocarbostyril and 14.7 g of 4-methoxy.

  benzylamine and heated at 170-200 C for 5 h. Excess 4-methoxybenzylamine is distilled off under reduced pressure and the residue is isolated and purified by column chromatography on silica gel followed by recrystallization from ethanol.

  to obtain 0.35 g of 6- [4- (4-methoxybenzyl) -1-piperazinyl] -3.4-

  dihydrocarbostyril, F. 196-198 C, colorless needles.

  Elemental analysis C (%) H (%) N (7) Calculated: 71.79 7.12 11.97 Found: 71, 65 6.98 12.10 Analogously to Example 128, the following are prepared: same compounds as those obtained in Examples 1, 2, 6, 15, 28-31, 39 and 42-49 above and Examples 143, 145, 147 and 148 hereinafter

  using the appropriate starting materials.

EXAMPLE 129

  A mixture of 14.5 g of 6- [bis (2-chloroethyl) amino] -3,4-dihydrocarbostyril, 8.0 g of 4-methoxybenzylamine and 70 ml of methanol is stirred under reflux for 15 hours. After cooling, 3.06 g of sodium carbonate are added to the reaction mixture and the mixture is stirred under reflux for 8 hours. After cooling, collect by

  filtered precipitated crystals and recrystallized in the étha-

  to obtain 8.1 g of 6- [4- (4-methoxybenzyl) -1-piperazinyl] -3.4-

  dihydrocarbostyril, F. 196-198 C, colorless needles.

  Elemental analysis C (%) H (%) N (%) Calculated: 71.79 7.12 11.97 Found 71.62 7.21 11.82 In a similar manner to Example 129, the same compounds are prepared as those obtained in Examples 1, 2, 6, 15, 28-31, 39 and 4249 above and 143, 145, 147 and 148 hereinafter using

  the appropriate starting materials.

EXAMPLE 130

  (a) stirring at about 160 ° C for 10 hours a mixture of

  81 g of 6-amino-3,4-dihydrocarbostyril and 82 g of ethylenechloro-

  hydrin. After cooling, it is added to the reaction mixture

  ml of aqueous NaOH solution to separate the organic layer.

  that it is then dried on KOH. After separation of KOH by filtration, the liquor is distilled under reduced pressure to give 90 g of 6- [bis (2-hydroxyethylamino] -3,4-dihydrocarbostyril.

  Compound production is confirmed by IR and NMR spectra.

  Elemental analysis C (M) H (%) N (%) Calculated: 62.40 7.20 11.20 Found: 62, 27 7.09 11.34 (b) Reacted for about 6 h at 160-170 C a

  mixture of 9 g of 6- [bis- (2-hydroxyethyl) amino] -3,4-dihydrocarbon

  styryl, 4.1 g of 4-methoxybenzylamine and 7.6 g of polyphosphoric acid

  prepared from 3.8 g of phosphorus pentoxide and 3.8 g of phosphoric acid. After cooling, add drop to

  drop to the reaction mixture about 500 ml of water to dissolve it.

  The solution is neutralized with an aqueous solution

  of 48% sodium hydroxide and extracted with chloroform.

  After drying the potassium carbonate extract, the chloroform is distilled off. The recrystallization of

  residue in ethanol gives 8 g of 6- [4- (4-methoxybenzyl) -1-piperine

  razinyl] -3,4-dihydrocarbostyril, mp 196-198 ° C, colorless needles.

  Elemental analysis C (%) H (%) N (%) Calculated: 71.79 7.12 11.97 Found: 71, 91 7.01 11.86 In a similar manner to Example 130, the same compounds are prepared than those obtained in Examples 1, 2, 6, 15, 28-31, 39 and 4249 above and 143, 145, 147 and 148 hereinafter using

  appropriate starting materials.

EXAMPLE 131

  The mixture is stirred at 165.degree.-175.degree. C. for 4 h 30 min. With a mixture of 2.7 g of 6-amino-3,4-dihydrocarbostyril, 9 g of N, N-bis (2-hydroxyethyl) -3. 4-dimethoxybenzamide and 8.6 g of 85% phosphoric acid. After cooling, about 50 ml of water are added dropwise to the reaction mixture to dissolve it. The solution is neutralized with an aqueous solution

  of 48% sodium hydroxide and chloroform was added.

  * After drying the extract on potassium carbonate, we ..

  flush chloroform by distillation. The recrystallization of

  residue in the ethanol-chloroform mixture gives 4.7 g of 6- [4- (3,4-

  dimethoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril,

Mp 238-239.5 ° C, colorless granules.

  Elemental analysis C (M) H (%) N (%) Calculated: 66.84 6.33 10.63 Found: 66, 95 6.23 10.51 In a similar manner to Example 131, the same compounds are prepaze than those obtained in Examples 1, 2 and 4-91 above and 143,

  , 147 and 148 hereinafter using appropriate starting materials.

EXAMPLE 132

  (a) To a solution of 7.02 g of p-aminoaniline in ml of toluene was added 9.12 ml of triethylamine and stirred

  at 80C by adding dropwise a solution of 11 g of chlorine

  of P-bromopropionyl in 30 ml of toluene. After reaction for 30 minutes, a colored resinous material is formed which is formed and the reaction mixture is washed with water and dried. Removal of the solvent by distillation gives 10.1 g of N- (D-bromopropionyl) -p-aminoaniline as an oily product. The production of the compound is confirmed by the spectra

IR and NMR.

  Elemental analysis C (%) H (%) N (%) Calculated: 44.44 4.53 11.52 Found: 44, 32 4.61 11.43 (b) A mixture of 14 0 g of N- (β-bromopropionyl) -p-aminoaniline, 18 g of bis (ebromoethyl) amine monobromide and 70 ml of methanol. After cooling, 3.06 g of potassium carbonate are added to the reaction mixture and the mixture is stirred under reflux for 8 hours. After cooling, the crystals formed are collected by filtration and washed with methanol to

  obtain 5.3 g of N- (β-bromopropionyl) -p-piperazinylaniline.

  The production of the compound is confirmed by the IR and NMR spectra. Elemental analysis C (%); H (%) N (%) Calculated: 50.00 5.77 13.46 Found: 49, 91 5.69 13.41 (c) A suspension of

  2.2 g of N- (1-bromopropionyl) -p-piperazinylaniline and 28 g of chlorine

  anhydrous aluminum chloride sprayed in 50 ml of carbon disulfide.

  The reaction mixture is poured into ice-cold water and the precipitate is collected by filtration, washed with water and then with ether and is transformed into hydrobromide and then recrystallized from the mixture.

  methanol-water to obtain 0.9 g of 6- (1-piperane) monobromide

  zinyl) -3,4-dihydrocarbostyril, m.p. 289-293 "C (decomp.) (methanol-

water), colorless needles.

  Elemental analysis C (%) H (%) N (%) Calculated: 50.00 5.77 13.46 Found: 49. 96 5.81 13.51 Compounds than those 147 and 148 below

EXAMPLE 133

  Analogously obtained using them in Example 132, the same Examples 2-92 above and 143, 145 are prepared.

appropriate starting materials.

  It is stirred while cooling in an ice bath a mixture

  of 2,6 g of 3,4-dimethoxybenzoic acid, 1.65 g of 1,8-diazabicyclo

  [5.4.0] undecene-7 and 100 ml of DMF by adding dropwise 1.5 ml of isobutyl chloroformate. When the addition is complete, the mixture is stirred for 30 minutes and a solution of 2.3 g is added thereto.

  6- (1-piperazinyl) -3,4-dihydrocarbostyril in 40 ml of DMF.

  After stirring at room temperature for 5 hours, the solvent is distilled off and the residue is extracted with about 300 ml of chloroform. The extract is washed successively with a dilute aqueous solution of NaHCO 3, water, dilute hydrochloric acid and water. The chloroform is distilled off and the residue is recrystallized from ethanol-chloroform.

  to obtain 1.7 g of 6- [4- (3,4-dimethoxybenzoyl-1-piperazinyl) -3,4-

-

  dihydrocarbostyril, mp 238-239.5 ° C, colorless granules.

  Elemental analysis C (M) H (%) N (x) Calculated: 66.84 6.33 10.63 Found: 66, 72 6.45 10.52 In a similar manner to Example 133, the same compounds are prepared than those obtained in Examples 4, 7-14, 16, 26, 32-38, 41, 5061 and 63-91 using appropriate starting materials.

EXAMPLE 134

  A mixture of 1.22 ml is stirred at 50-60 ° C. for 2 hours.

  of acetic anhydride and 0.5 ml of formic acid. After cooling

  At room temperature, 1.0 g of 5-piperazinyl-3,4-dihydrocarbostyril are added portionwise to the reaction mixture; the product solidifies during this operation. 5 ml of dichloromethane are added to the solid and the mixture is stirred at room temperature for 2 hours. A large amount of water is then added and the mixture is extracted with chloroform. After washing with water, the extract is dried over anhydrous sodium sulfate and then the chloroform is distilled off. The recrystallization of the residue in

  methanol gives 420 mg of 5- (4-formyl-1-piperazinyl) -3,4-dihydro-

  carbostyril, mp 263-265 C, colorless granules.

  Elemental Analysis C (%) H () N (%) Calculated 64.84 6.61 16.21 Found: 64.64 6.57 16.22 Analogous to Example 134, the same compound was prepared as that obtained in Example 62 using a product

appropriate starting point.

EXAMPLE 135

  3.5 g of 2-nitro-5-piper hydrochloride are dissolved

  ethyl razinylcinnamate in a solvent mixture consisting of ml of ethanol and 45 ml of water and the solution is adjusted to about pH 7 with aqueous sodium hydroxide. 2 g of Raney nickel is added as a catalyst to the solution and it is placed in a glass autoclave and then stirred at 80 ° C. for 4 hours under a hydrogen pressure of 5 bar. After removing the hydrogen, the reaction mixture is taken up and the catalyst is separated off. The solution is concentrated to dryness and methanol is added to the residue.

  to precipitate crystals which are then collected by filtration.

  and recrystallized from methanol to give 1.3 g of

  6- (1-piperazinyl) -3,4-dihydrocarbostyril, m.p. 224-231.5 ° C.

EXAMPLE 136

  8.8 g of 2-nitro-5- [4- (3,4-dimethoxybenzoyl) -1-pipazolyl] cinnamic acid are dissolved in 88 ml of DMF and 1.6 g of Raney nickel are added to the solution as the solution. catalyst and reacted at 80 ° C for 4 h under hydrogen pressure

  of 3 bars in a Parr apparatus. After removal of the hydro-

  After the reaction, the reaction mixture is taken up and the catalyst is separated off.

  The solution is concentrated to dryness and methanol is added to the residue to precipitate crystals which are then collected by filtration and recrystallized from DMF and then into the mixture.

  chloroform-methanol, to obtain 5.8 g of 6- [4- (3,4-dimethoxy)

  benzoyl-p -razinyl-3,4-dihydrocarbostyril, m.p. 238-239.5 ° C.

  In a similar manner to Example 36, the same mimics as those obtained in Examples 2,4-49; 64-66,73-87,90 and 91 are prepared;

  above and 145 and 147 hereinafter using appropriate starting materials.

EXAMPLE 137

  To a suspension of 1.0 g of 6- (1-

  piperazinyl) -3,4-dihydrocarbostyril in 10 ml of DMF, 296 mg of sodium bicarbonate are added and the mixture is stirred at room temperature.

  ambient for 30 min to convert the compound to 6- (1-piperazol)

  3,4-dihydrocarbostyril to which 0.62 ml of triethylamine is added.

  A solution is then slowly added dropwise to the mixture.

  605 mg of 4-acetyloxybenzoyl chloride in 5 ml of DMF.

  When the addition is complete, the mixture is stirred at room temperature.

  room temperature for 1 h. The reaction mixture is poured into a large amount of water and extracted with water. The extract is washed successively with a saturated aqueous solution of sodium bicarbonate and chloroform and then dried over anhydrous sodium sulfate. The chloroform is distilled off to obtain

  6- [4- (4-acetyloxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril.

  Elemental analysis C (%) H (%) N (%) Calculated: 67.16 5.89 10.68 Found: 67, 04 5.98 10.49

EXAMPLE 138

  (a) To a solution of 11 g of p- [4- (3,4-dimethoxybenzoyl) -

  1-piperazinyl] aniline in 100 ml of benzene is added 4.56 ml of triethylamine and heated to reflux with stirring dropwise a solution of 3.94 g of 9-methoxyacryl chloride in 20 ml of benzene. When the addition is complete, the mixture is refluxed for 1 hour. After the end of the reaction, the reaction mixture is washed with water and dried. The solvent is distilled off and the residue is purified by column chromatography.

  silica gel to obtain 10 g of N- (O-methoxyacryloyl) -p-

  [4- (3,4-dimethoxybenzoyl) -l-piperazinyl] aniline. Elemental analysis C (M) H (M) N (') Calculated: 64.92 6.40 9.88 Found: 64.77 6.51 9.75

  (b) 5 g of N - (> methoxyacryloyl) -

  p- [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] aniline to 50 ml of 60% 2SO4 with stirring at room temperature. After continuing the reaction for 2 hours, the reaction mixture is neutralized by

  NaOH ION to precipitate crystals which are collected by filtration

  and washed with water. The recrystallization of crystals in

  a chloroform-methanol mixture gives 230 mg of 6- [4- (3,4-dimethoxy)

  benzoyl) -1-piperazinyl] carbostyril, mp 265-266.5 ° C (decomp.),

yellow granules.

  Elemental analysis C (Mo) H (%) N (%) Calculated: 67.16 5.89 10.68 Found: 67, 08 5.78 10.81 In analogy to Example 138, the same compounds are prepared than those obtained in Examples 50-53, 55-63, 67-72,

  88 and 89 using appropriate starting materials.

EXAMPLE 139

  A mixture of 5.6 g is refluxed for 5 hours.

  of 6-bromo-3,4-dihydrocarbostyril, 2.9 g of 4- (3,4-dimethoxy)

  benzoyl) -1-piperazine, 1.8 g of potassium carbonate, 0.2 g of copper powder and 60 ml of 3-methoxybutanol. We filter the

  mixture and the filtrate is concentrated to dryness under reduced pressure.

  The residue is extracted with the methanol-chloroform mixture and then the chloroform layer is distilled. The residue thus obtained is purified by preparative thin layer chromatography on silica gel and recrystallized from chloroform-ethanol.

  to obtain 489 mg of 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -

  3,4-dihydrocarbostyril, mp 238-239.5 ° C, colorless granules.

  Elemental Analysis C (%) H (%) N (%) Calcd for: 66.84 6.33 10.63 Found: 66.70 6.48 10.53

  In a similar manner to Example 139,

  the same compounds as those obtained in Examples 1, 2

  and 4-91 above and in Examples 143, 145, 147 and 148 below.

  after using appropriate starting materials.

EXAMPLE 140

  1 g of 3- [2-amino-5- {4- (3,4-

  dimethoxybenzoyl) -1-piperazinyl] phenyl] propionic in a chloroform-methanol solvent mixture and added to the solution

  1 ml of concentrated hydrochloric acid. The resultant mixture is stirred

  for 1 hour at room temperature. After distilling off the solvent, the residue is recrystallized

  the ethanol-chloroform mixture to give 500 mg of 6- [4- (3,4-

  dimgthoxybenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril.

Mp 238-239.5 ° C, colorless granules.

  In a similar manner to Example 140,

  the same compounds as those obtained in Examples 1, 2, 4-49, 6466 and 73-87 described above and in Examples 143, 145, 147 and 148 described hereinafter, using products

appropriate starting points.

EXAMPLE 141

  10 g of 3- [2-aminoacetyl-5- acid are dissolved

  [4- (3,4-Dimethoxybenzoyl) -1-piperazinylphenyl] propionic acid

  in 100 ml of diphenyl ether and the solution is stirred at 90-100 C.

  After continuing the reaction for 8 hours, pour the mixture

  in water and the crystals are collected by filtration.

  precipitated rates. The crystals thus obtained are subjected to chromium

  matography on silica gel column to separate them and then recrystallized in the methanol-chloroform mixture

  to obtain 1.2 g of 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -

carbostyril.

  265-266.5 ° C (decomp.), Yellow granules.

  In a similar manner to Example 141, the same compounds as those obtained in Examples 50-53, -63 and 67-72 described above and in Examples 143 and 148 are prepared.

  hereinafter using appropriate starting materials.

EXAMPLE 142

  5 g of 2-amino-5- [4- (3,4-dichloroacetic acid)

  dimethoxybenzoyl) -1-piperazinyl] cinnamic in 50 ml of DMF and 0.5 g of 5% palladium on carbon are added to the solution. The mixture is reacted at 80 ° C. for 4 hours under a hydrogen pressure of 3 bar using a Parr apparatus.

  separation of hydrogen, the contents of the

  mera. The catalyst is separated, the reaction mixture is concentrated

  at half its initial volume and poured into a large volume of water. The crystals are collected by filtration

  precipitated and recrystallized from the ethanol-

  chloroform to obtain 2.9 g of 6- [4- (3,4-diofthoxybenzoyl) -1-

  piperazinyl] -3,4-dihydrocarbostyril.

Mp 238-239.5 ° C, colorless granules.

  In a similar manner to Example 142, the same compounds as those obtained in Examples 1, 2, 4-49, 64-66, 73-87 described above and in Examples 145 and 147 are prepared.

  hereinafter using appropriate starting materials.

EXAMPLE 143

  A mixture is stirred at 80 ° -90 ° C. for 3 hours.

  25 g of 6-aminocarbostyril, 50 g of bis (P-hydrobromide)

  bromoethyl) amine and DMF. After cooling to room temperature, 8.2 g of Na 2 CO 3 are added to the mixture.

  it is stirred at 80-90 ° C. for 4 hours. After cooling down to

  at room temperature, the crystals obtained by filtration are collected by filtration.

  precipitated, washed with ethanol and dried to obtain 22 g of

  6- (1-piperazinyl) carbostyril hydrobromide F.> 300C, crystals

  pale yellow rhombic rate (water-ethanol).

EXAMPLE 144

  2.0 g of hydrobromide salt are suspended

  6- (1-piperazinyl) carbostyril in 20 ml of DMF. After addi-

  2.34 ml of triethylamine is added dropwise at

  mix a solution of 1.43 g of 3,4-methylene chloride

  dioxybenzoyl in 2 ml of DMF. When the addition is complete, the mixture is stirred at room temperature for 30 minutes and the reaction mixture is poured into a large amount of water. The crystals formed are collected by filtration and dried. The crystals are then purified by column chromatography on silica gel and recrystallized from the mixture.

  chloroform-methanol to obtain 1.9 g of 6- [4- (3,4-methylene)

  dioxybenzoyl) -l-piperazinyl] carbostyril.

  F. 266-267 C (decomp.), Yellow powder.

EXAMPLE 145

  A mixture of 23 g of 7-amino-3,4-dihydrocarbostyril and 48 g of hydrobromide is refluxed for 8 hours.

  of bis (p-bromoethylamine and 200 ml of methanol.

  At room temperature, 7.52 g of sodium carbonate are added to the mixture and the mixture is heated under reflux with stirring.

  for another 8 hours. After having distilled the methanol

  under reduced pressure, isopropanol is added to the residue. After cooling, the precipitated crystals are collected by filtration and the mixture is recrystallized three times in ethanol.

  to obtain 15 g of 7- (1-piperazinyl) -3,4-dihydrobromide

hydrocarbostyrile.

Mp 174-177 ° C, colorless granules.

EXAMPLE 146

  To a solution of 800 mg of 7- (1-piperazinyl) -3,4-dihydrocarbostyril hydrobromide in 10 ml of DMF was added 1.2 ml of triethylamine and then a solution of 730 mg was added dropwise to the mixture with stirring. of chloride

  of 4-chlorobenzoyl in 2 ml of DMF. After the end of the

  The mixture is stirred at room temperature for 30 minutes.

  The reaction mixture is poured into a large amount of water.

  The crystals formed are collected by filtration,

  washed with water and dried. The crystals are purified by chromatography

  matography on silica gel column and recrystallize

  in the chloroform-methanol mixture to obtain 700 mg of 7- [4-

  (4-chlorobenzoyl) -l-piperazinyl] -3,4-dihydrocarbostyril.

Mp 289-291 ° C, colorless powder.

EXAMPLE 147

  7.5 g (46.2 mmol) of 8-amino-3,4-dihydrocarbostyril and 15.9 g (50.8 mmol) of bis (β-bromoethyl) amine hydrobromide are suspended in methanol and the refluxing with stirring for 9 h. After addition of 2.5 g of sodium carbonate, the reaction mixture is refluxed again for 8 hours with stirring and stirred in an ice bath for 1 hour. The precipitated crystals are collected by filtration. The crude crystals thus obtained are recrystallized from methanol-ether to give 2.4 g.

  of 8- (1-piperazinyl) -3,4-dihydrocarbostyril hydrobromide.

F.> 300 C, colorless needles.

EXAMPLE 148

  15.47 g (96.6 mmol) of aminocarbostyril and 33 g (106 mmol) are suspended in DMF.

  of bis (P-bromoethyl) amine hydrobromide and the suspension is stirred

  at 70-80 ° C. for 10 hours. After addition of 5.1 g of carbon

  sodium salt, the reaction mixture is stirred at the same temperature

  than above for 7 h. After having removed the solvent by distillation under reduced pressure, methanol is added

  to the residue to crystallize it. We recrystallize the crystals

  crude levels thus obtained in the methanol-ether melt for

* obtain 5.1 g of 8- (1-piperazinyl) carbostyril hydrobromide.

F.> 300 C, colorless flakes.

EXAMPLE 149

  0.7 g (2.26 millimoles) of 8- (1-piperazinyl) carbostyril and 0.2 g of sodium bicarbonate are suspended.

  sodium in 5 ml of DMP and the suspension is stirred at room temperature.

  room temperature for 30 minutes. 0.4 ml of triethylamine is added to the resulting mixture and a solution of 0.47 g of 2-chlorobenzoyl chloride in 5 ml of DMF is added dropwise, followed by stirring at room temperature for 30 minutes. We pour

  the reaction mixture in saturated aqueous bicarbonate solution

  sodium nate and extracted with chloroform. The organic layer is washed with water and then with saturated aqueous sodium bicarbonate and dried over sodium sulfate. After driving the soil

  by distillation, ether is added to the residue for the crystalline

  Liser. The crystals thus obtained are recrystallized from ethanol to give 0.24 g of 8- [4- (2-chlorobenzoyl) -1-piperazinylcarbostyril.

  Mp 239-240.5 ° C, colorless needles.

PHARMACOLOGICAL TRIALS

  Preparations of sinoatrial bulb isolated and under perfusion.

  We perform experiments on bastard dogs

  adults of both sexes. The Chinese bulb preparations are obtained

  atrial from dogs weighing 8-13 kg, anesthetized with 30 mg / kg i.v. sodium pentobarbital, given 1000 U / kg i.v. heparin, then bled. The preparation, consisting mainly of the atrium

  right in a cold Tyrodian solution, is placed in an enve-

  a glass lump containing water maintained at approximately 380 ° C and circulated by the right coronary artery with a cannula with the blood of a donor dog at a constant pressure of 100 mm Hg. donors have a body weight of 18-27 kg and are anesthetized with 30 mg / kg iv sodium pentobarbital. Sodium heparin is administered at a dose of 1000 U / kg iv. right atrium by means of a strain measurement transducer. The right atrium is loaded with a weight of about 1.5 grams. The rhythm of the bulb is measured by a cardiotachymeter controlled by the developed tension of the right atrium. Blood flow is measured through the right coronary artery using an electromagnetic flowmeter. We record the developed voltage, the rhythm of the bulb and the flow

  graphically by means of a recording device

  in ink. The details of the preparation have been described by

  Chiba et al. (Japan J. Pharmacol 25, 423-439, 1975;

  Schmiedberg's Arch. Pharmacol. 289, pp. 315-325) 1975. Injected

  30 μl of the compounds arterially in 4 s. Inoxic effects

  tropes of the compounds are measured as a percentage of the tension developed before the injection of the compounds. The effects of the compounds on the rate of bu 1 b e (beats / min) or blood flow (ml / min) are expressed as the difference between the values before and

after the injection of the compounds.

  The results obtained are shown in Table 1.

Compound tried.

  6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbyl

  styryl, 2. 6- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, 3- (4-acetyl-1-piperazinyl) -3,4-dihydrocarbostyril, 4-6- [4- 4-methoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyril

  5. 6- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbo

styrile,

  6. 5- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbo

  styryl, 7- [4- (4-chlorobenzyl) -1-piperazinyl] -3,4-dihydrocarbostyril, 8- (1-piperazinyl) -3,4-dihydrocarbostyril, 9- 6- [4- ( 4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, 10. 6- [4- (4-aminobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  11. 6- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril, 12. 6- [4- (4-bromobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, 13. 6- [4- (4-cyanobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  14. 5- [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbo

styrile,

  15. 8-Methoxy-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro-

carbostyril

  16. 1-Methyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril, 17. 6- (4-furoyl-1-piperazinyl) -3,4-dihydrocarbostyril, 18. 6- (4-benzoyl-1-piperazinyl) -3,4-dihydrocarbostyril,

  19. 1-Benzyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro-

carbostyril hemihydrate,

  20. 6- [4- (2-phenethyl) -1-piperazinyl] -3,4-monhydrochloride

  dihydrocarbostyril, 21. 6- (formyl-1-piperazinyl) -3,4-dihydrocarbostyril, 22. 6- (4-ethoxycarbonylmethyl-1-pipdrazinyl) -3,4-dibydrocarbostyril, 23. 6- (4-methoxycarbonyl) p -diprazinyl) -3,4-dihydrocarbostyril, 24. 6- [4- (3chlorobenzoyl) -1-piperazinyl-3,4-dihydrocarbostyril, 25. 6- (4-methanesulfonyl) -1-pipdrazinyl) -3,4-dihydrocarbostyril , 26. 6-F4- (4-methylbenzyl) -1-pipdrazinyl] -3,4-dihydrocarbostyril,

  27. monohydrochloride monohydrate of 5- [4- (3,4-dichlorobenzoyl) -1-

  piperazinyl] -3,4-dihydrocarbostyril, 28. 6- [4- (3,5-dinitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, 29. 6- (4-allyl-1-piperazinyl) -3,4-dihydrocarbostyril , 5- [4- (2-propynyl) -1-piperazinyl] -3,4-dihydrocarbostyril,

  21. 5- (4-ethyl-1-piperazinyl) -3,4-dihydro-hydrochloride

carbostyril

  32. 1-Allyl-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-di-

hydrocarbostyril hemihydrate,

  33. 1- (2-Propynyl) -6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-

  dihydrocarbostyril, 34. 5- [4- (p-toluenesulfonyl) -1-piperazinyl] -3,4-dihydrocarbostyril, 35. 6- [4- (4-methylthiobenzoyl) -1-piperazinyl] carbostyril, 36. 6- [4- (3-pyridylcarbonyl) -l-pipdrazinyl] -3; 4dihydrocarbostyrile,

  37. 6- [4- (4-Methoxyphenylacetyl) -1-piperazinyl] -3,4-dihydrocarboxylate

  styryl hemihydrate, 38. 6- (4-phenylpropionyl-1-piperazinyl) -3,4-dihydrocarbostyril, 39. 8- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] carbostyril, 40. 5- [4- ( 4-hydroxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril, 41. 6- [4- (3,4-dimethoxybenzoyl) -1-pipdrazinyl] carbostyril, 42. 6- [4- (3-chlorobenzoyl) -1- piperazinyl] carbostyril, 43. 6- [4- (3,4-methylenedioxybenzoyl-1-piperazinyl) carbostyril, 44. 6- [4- (4-nitrobenzoyl) -1-piperazinyl] carbostyril, 45. 6- [4- (4) 1-cyanobenzoyl) -1-piperazinyl] carbostyril, 46. 6- (4-benzoyl-1-pipdrazinyl) carbostyril, 47. 6-F4- (4-chlorobenzoyl) -1-piperazinyl] carbostyril, 48. 6- [4- (3-chlorobenzoyl); , 4,5trimethoxybenzoyl) -1-pipdrazinyl] carbostyril, 49. 6- (4-methoxycarbonyl-1-piperazinyl) carbostyril, 50. 6- [4- (4-aminobenzoyl) -1-piperazinyl] carbostyril, 51. 6- [4 - (4-formyl) -l-piperazinyl] carbostyril

  52. 5- (4-Benzyl-1-piperazinyl) -3,4-dihydrohydrochloride

carbostyril

  53. 7- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydro-

  carbostyril, 54. 7- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, 55. 7- [4- (2-chlorobenzoyl) -1-piperazinyl] -3, 4dihydrocarbostyril, 56. 7- (4-ph-nylpropionyl-1-piperazinyl) -3,4-dihydrocarbostyril,

  57. 7 - [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl-3,4-dihydrocarbyl)

styril, 58. papaverine (control),

59. amurinone (control).

T A B L E A U 1

  Compound Tries Dose Variation in Coronary Blood Flow Contraction Rate (nmoles) Atrial Muscle,% (Ml / Min)

1,100 79.6 1,2

2 100 100 0.8

3,300 96 0.8

4,100 25

300 83 1.6

6,300 35.7 0.8

7,100 8.0 -

8 100 5.7 0.4

9 100 60 1.0

300 50.0 1.2

11 100 46.9 1.6

12,300 33 1.6

13,300 63.2 0.6

14,300 65.9 1.0

1000 25 1.2

16,300 10.7 2.0

17 100 53.8 1.2

18 300 40 1.6

19,300 17.9 2.0

500 18.5 0.8

21 100 122.2 0.4

  T A B L E A U 1 (cont'd) Test Compound Dose Variation in Coronary Blood Flow Contraction Rate (nmoles) atrial muscle,% 7. (Ml / min)

22 1000 15.3 0.4

23 100 25.0 0.4

24 100 57.1 0.2

100 24.1 0.3

26 100 19.0 0.2

27 300 20.0 0.2

28,300 14.3 1.4

29 100 20.3 0.2

100 21.4 0.3

31 100 20.7 0.2

32 300 13 1.2

33 300 12 0.8

34,300 42 1.1

41 300 145 1.4

52,300 37.8 -

58 100 73.8 2.4

  Preparations of isolated papillary muscle and blood perfusion.

  Experiments are conducted on adult bastard dogs of both sexes. The excised papillary muscle preparations with the ventricular septum are obtained from dogs weighing 8-13 kg, anesthetized with 30 mg / kg of iv sodium pentobarbital, given 1000 U / kg of iv heparin, and then bled, the preparation consisting essentially of the papillary muscle excised with the ventricular septum in a cold Tyrode solution. The preparation is placed in a glass envelope

  containing water maintained at approximately 38 C and circulated

  cross-flow from the right coronary artery cannulated with the blood of a donor dog at a constant pressure of 100 mm Hg. Dogs used as donors have BLEAU 2 (contd) Compound tried Dose Variation of the ( nmoles) contraction of the atrial muscle,%

42,300 56.0

43,300 75.0

44,300 32.3

300 45.5

46,200 30.0

47 1000 28.0

48 to 1000 38.3

49,300 56.7

100 15.8

51 100 73.3

53 1000 13.2

54 1000 11.5

1000 17.4

56 1000 14

57 1000 14.2

59 1000 30.8

PREPARATION EXAMPLE 1

  6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -

  3,4-dihydrocarbostyril starch magnesium stearate Lactate

each the above composition.

EXAMPLE OF PREPARATION 2

  6- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-

  Variation in coronary blood flow (ml / min) 2.5 1.5 3.5 0.5 3.5 3.5 3, 5 mg 132 mg 18 mg mg es tablets having - ainyarocarbostyril 10 mg starch 127 mg magnesium stearate 18 mg Lactate 45 mg Tablets are conventionally prepared with

each the above composition.

  TA i T A B L E A U 2 (cont'd) Test Compound Dose Variation of Flow Variation (nmoles) Contraction of Coronary Blood [es] _ Atrial Muscle _'i (ml / min)

42,300 56.0 2.5

43 -300 75.0 1

44,300 32.3 3

300 45.5 1

46 200 30.0 1.5

47 1000 28.0 4

48 1000 38.3 -

49 300 56.7 3.5

100 15.8 0.5

51 100 73.3 1

53 1000 13.2 3.5

54 1000 11.5 4

1000 17.4 3.5

56 1000 14 3

57 1000 14.2 3.5

59 1000 30.8 -

PREPARATION EXAMPLE 1

  6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -

  3,4-dihydrocarbostyril 5 mg Starch 132 mg Magnesium stearate 18 mg Lactate 45 mg Tablets having

each the above composition.

EXAMPLE OF PREPARATION 2

  6- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-

  Dihydrocarbostyril 10 mg Starch 127 mg Magnesium Stearate 18 mg Lactate 45 mg Tablets having

each the above composition.

EXAMPLE OF PREPARATION 3

  6- [4- (4-nitrobenzoyl) -l-piperazinyl] -3,4-

  dihydrocarbostyril 500 mg Polyethyleneglycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan monooleate 0.4 g Sodium metabisulphite 0.1 g Methyl parahydroxybenzoate 0.18 g Propyl parahydroxybenzoate 0.02 g Water Distilled for injection 100 ml The above p-hydroxybenzoates, sodium metabisulfite and sodium chloride are dissolved in distilled water at 80 ° C. with stirring. The resulting solution is cooled to 40 ° C. and

  dissolves polyethylene glycol and polyoxyethylene monooleate

  sorbitan. Distilled water for injection is then added to adjust the final volume. The mixture is filtered using a suitable filter paper to sterilize it and then filled with

  ampoules of 1 ml, thus forming the preparation for injection.

EXAMPLE OF PREPARATION 4

  6- [4- (3,4-dimethoxybenzoyl) -l-piperazinyl] carbo-

  styril 5 mg starch 132 mg magnesium stearate 18 mg lactose 45 mg Tablets having

each the above composition.

  It is understood that the invention is not limited

  to the preferred embodiments described above as illus-

  tion and that the person skilled in the art may make various modifications

  tions and various changes without departing from the framework and

the spirit of the invention.

Claims (28)

R E V E N D I C A T I 0 N S   1 - Derivatives of carbostyril, characterized in that they correspond to the general formula N N-R (I) 2 i'1 R R   wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or lower phenylalkyl; R2 represents a hydrogen atom or a lower alkoxy group, R represents a hydrogen atom or a lower alkanoyl group,   a furoyl group, a pyridylcarbonyl group, an alkane-   lower sulfonyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl group, a phenylsulfonyl group which may be substituted by a lower alkyl group on its benzene ring, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower phenylcarbonyl group, a lower phenylalkyl group, or a lower phenylalkanoyl group, each of said phenylcarbonyl, lower phenylalkyl and lower phenylalkanoyl groups may be substituted on its benzene ring by 1 to 3 substituents selected from halogen atoms, lower alkoxy groups, alkyl groups; lower, cyano, nitro, amino, hydroxy, lower alkanoylamino, lower alkylthio and lower alkanoyloxy or lower alkylenedioxy group; and the 3-4 bond of the carbostyril ring is a single or double bond.   2 - Carbostyril derivatives according to the claim   1, characterized in that R represents a phenylcarbonyl group   which can be substituted on its benzene ring by 1 to 3   selected from halogen atoms, alkoxy groups   lower alkyl, cyano, nitro, amino, hydroxy, alkanoyl-   lower amino, lower alkylthio and lower alkanoyloxy,   or by a lower alkylenedioxy group.   3 - Carbostyril derivatives according to claim   cation 1, characterized in that R represents a lower alkanoyl, furoyl, pyridylcarbonyl, lower alkoxycarbonyl or a lower phenylalkanoyl group, which may be substituted on its benzene ring by 1 to 3 substituents chosen from halogen atoms and alkoxy groups. lower, lower alkyl, cyano, nitro, amino, hydroxy, lower alkanoylamino, alkylthio   and lower alkanoyloxy, or with an alkylene group lower dioxy.   4 - Carbostyril derivatives according to claim   1, characterized in that R 3 represents an alkane group   lower sulfonyl or a phenylsulfonyl group that can be   substituted on its benzene ring by a lower alkyl group.   - Carbostyril derivatives according to Claim 1, characterized in that R represents a hydrogen atom or a lower alkoxycarbonylalkyl, lower alkyl, lower alkenyl, lower alkynyl group or a lower phenylalkyl group which may be substituted on its core   benzene with 1 to 3 substituents selected from halogen atoms   gene and lower alkoxy, lower alkyl, cyano, nitro, amino, hydroxy, lower alkanoylamino, lower alkylthio groups   and lower alkanoyloxy or lower alkylenedioxy group.   6 - Carbostyril derivatives according to the claim   2, characterized in that R1 and R2 each represent a hydrogen atom.   7 - Carbostyril derivatives according to the claim 1 2   2, characterized in that R and R are each different from hydrogen.   8 - Carbostyril derivatives according to the claim   3, characterized in that R and R each represent a hydrogen atom.   9 - Carbostyril derivatives according to the claim   3, characterized in that R1 and R2 are each different from Hydrogen.   - Carbostyril derivatives according to the claim   6, characterized in that the 3-4 bond of the carbostyril ring is a simple link.   11 - Derivatives of carbostyril according to the claim   6, characterized in that the 3-4 bond of the carbostyril ring is a double bond.   12 - Carbostyril derivatives according to the claim   10 or 11, characterized in that the substituent of formula -N> -R3   is in position 5 or 6 of the carbostyril ring.   13 - Carbostyril derivatives according to the claim   10 or 11, characterized in that the substituent of formula _ <\ -R _3   is in position 7 or 8 of the carbostyril nucleus.   14 - Carbostyril derivatives according to the claim   12, characterized in that R 3 represents a benzoyl group which is substituted on its benzene ring by 1 to 3 substituents selected from halogen atoms and lower alkoxy groups,   or by a lower alkylenedioxy group.   15 - The compound according to claim 14, characterized   it consists of 6- [4- (3,4-dimethoxybenzoyl) -1-   piperazinyl] -3,4-dihydrocarbostyril.   The compound of claim 14, wherein   characterized by being 5- [4- (3,4-dimethoxybenzoyl) -1-piperine rasinyl] -3,4-dihydrocarbostyril.   17 - Compound according to claim 14,   in that it consists of 6- [4- (4-methoxybenzoyl) -1-piperane zinyl3-3,4-dihydrocarbostyril.   18-compound according to claim 12, characterized   in that it consists of 6- [4- (4-aminobenzoyl) -1-piperazinyl] - 3,4-dihydrocarbostyril.   19 - Compound according to claim 14, characterized   in that it consists of 6- [4- (3,4-methylenedioxybenzoyl) -1-   piperazinyl] -3,4-dihydrocarbostyril.   Compound according to claim 8, characterized   rised in that it consists of 5- (4-formyl-1-piperazinyl) -3,4-   dihydrocarbostyril. 21 - Compound according to claim 14, characterized   rised in that it consists of 6- [4- (4-chlorobenzoyl) -1-piperazinyl] - 3,4-dihydrocarbostyril.   22. Compound according to claim 14, characterized   in that it consists of 6- [4- (3,4-dichlorobenzoyl) -1-piperazi- nyl] -3,4-dihydrocarbostyril.   23 - Compound according to claim 12, characterized   in that it consists of 6- [4- (3,4-dimethoxybenzoyl) -1-piperine razinyl] carbostyril.   24 - Compound according to claim 12, characterized   in that it consists of 6- [4- (3,4-methylenedioxybenzoyl) -1- piperazinyl] carbostyril.   Compound according to claim 12, characterized   in that it consists of 6- [4- (3-chlorobenzoyl) -1-piperazinyl] - carbostyril.   26 - Compound according to claim 12, characterized   rised in that it consists of 6- [4- (4-chlorobenzoyl) -1-piperazinyl] -   carbostyril. 27 - Process for the preparation of the carbostyril derivatives according to claim 1, characterized in that a compound of general formula (II) is reacted R R1   in which R and R2 are as defined above, with a compound of formula 3 CH2 x 3.- 22 (III) -.CH2CH2X 2 2   wherein R3 is as defined above.   28 - Process for the preparation of carbostyril derivatives of the general formula 41 N-R \ J (Ia) NOT R R R1   in which R, R2 and the 3-4 bond of the carbostyril ring are as defined in claim 1 and R3 represents a lower alkanoyl group, a phenylcarbonyl group which may have on its benzene ring 1 to 3 substituents selected from halogen and lower alkoxy, lower alkyl, cyano,   nitro, amino, lower alkanoylamino, lower alkylthio, alkanoyl-   lower oxy and hydroxy or a lower alkylenedioxy group, a   furoyl group, a pyridylcarbonyl group or an alkoxy group   lower carbonyl, characterized in that a compound of formula N / NH \ / X (IV) R R   wherein R, R and the 3-4 bond of the carbostyril ring are as defined above, with a compound of the general formula R3'X1 (V)   wherein R3 is as defined above and X represents a hydroxy group.   29 - Process for the preparation of the compounds of general formula N / '' NR3 " N N-R   - 0 (1b) o R1 wherein R, R and the 3-4 bond of the carbostyril ring are   as defined above and R represents an alkane group   lower sulfonyl, a lower alkoxycarbonylalkyl group, a phenylsulfonyl group which may be substituted for the benzene ring by lower alkyl, lower alkyl, lower alkenyl, lower alkynyl or a group   lower phenylalkyl which can be substituted on its benzene ring   with 1 to 3 substituents selected from halogen atoms and lower alkoxy, lower alkyl, nitro, cyano, amino, lower alkanoylamino, lower alkylthio, lower alkanoyloxy and hydroxy or lower alkylenedioxy groups, characterized in that a compound of formula N \\ 2 N (IV) is reacted 2 0 R 1   wherein R, R and the 3-4 bond of the carbostyril ring are as defined above with a compound of formula R3 "X2 (VI)   in which R is as defined above and X represents a halogen atom.   - Process for the preparation of a carbostyril derivative of formula (Ic) II R1 wherein R, R and the 3-4 bond of the carbostyril ring are 3 "'1 as defined above and R represents a group (alkoxy) lower) carbonyl lower alkyl, lower alkyl, lower alkenyl, lower alkynyl or lower phenylalkyl   which can be substituted on its benzene ring by 1 to 3   selected from halogen atoms and lower alkoxy, lower alkyl, nitro, cyano, amino, lower alkanoylamino, lower alkylthio, lower alkanoyloxy and hydroxy groups or lower alkylenedioxy groups, characterized in that a compound of formula - cH2 C2x \ 2 2 \ 1-1-CH2CH 2X (VIII)   in which R, R, and the 3-4 linkage of the carbostyril ring are as defined above, with a compound of formula 2R3 " NIH -R (IX) 3 "'1   wherein R3111 is as defined above.   31 - Process for the preparation of carbostyril derivatives of formula 249332O _-3 N -R3 "' (Id) R R1   wherein R, R and the 3-4 bond of the carbostyril ring are 3 "1 as defined above and R is lower alkoxycarbonylalkyl, loweralkyl, loweralkenyl, loweralkynyl or lower phenylalkyl   which can be substituted on its benzene ring by 1 to 3   selected from halogen atoms and lower alkoxy, lower alkyl, nitro, cyano, amino, lower alkanoylamino, lower alkylthio, lower alkanoyloxy and hydroxy groups or lower alkylenedioxy groups, characterized in that a compound of formula (XI) R1 wherein R, R and the 3-4 bond of the carbostyril ring are as defined above, with a compound of formula N H2-R (IX) 3 " '1   wherein R is as defined above.   32 - Process for the preparation of the carbostyril derivatives of formula (Ie) R2 R1 wherein R, R and R are as defined above and the 3-4 bond of the carbostyril ring is a single bond, characterized in that a compound of the formula ## STR2 ## is cyclized (XIII) R '1   wherein R, R2 and R are such that represents a halogen atom.   33 - Process for the above defined and R4 preparation of carbostyril derivatives of formula (Ih) R22 3   in which R, R and R are as defined above and the 3-4 bond of the carbostyril ring is a double bond, characterized in that a compound of formula N O-R3 (XXVI) AT R2   Wherein R, R2 and R are as defined above, A represents a group of formula R7-CH = CH-, wherein R7 represents a lower alkoxy group or a halogen atom, or a group of formula R 80 9 CH-CH2- R "   wherein R and R9 each represent a lower alkyl group or a CHqC- group.   34 - Process for the preparation of carbostyril derivatives of formula (i) N R R R   wherein R, R, R and the 3-4 bond of the carbostyril ring are as defined above; characterized in that a compound of formula X2 is reacted XXVII)   Wherein R, R2 and the 3-4 bond of the carbostyril ring are as defined above and X represents a halogen atom, with a compound of formula NH 3N-R (XXVIII)   wherein R3 is as defined above.   New medicaments useful in particular as cardiotonic agents, characterized in that they contain as active compound at least one carbostyril derivative according to the claim   1, or one of its pharmaceutically acceptable salts.   36 - Medicaments according to claim 35, characterized   in that they contain about 1 to 70% by weight, preferably 1-30% strength of the active product.   37 - Medicaments according to claim 35, or 36, characterized in that they are in unit dosage form   containing from 2 to 200 mg of the active product.